RB1

UniProt ID: P06400
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

RB1 encodes the retinoblastoma-associated protein (pRb / p105-Rb / p110-RB1), the founding member of the pocket protein family and a nuclear, chromatin-bound tumor suppressor. Its core evolved activity is to enforce the G1 restriction point by binding activator E2F transcription factors (E2F1/2/3) through the RB_A/RB_B pocket domains, masking their transactivation domains and recruiting chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases, polycomb factors) to E2F-target promoters required for S-phase entry. Activity is switched off by sequential cyclin-CDK phosphorylation: Cyclin D-CDK4/6 and Cyclin E-CDK2 progressively phosphorylate ~16 Ser/Thr sites, with an early reversible intermediate phosphorylation at T373/S608 followed by cooperative C-terminal hyperphosphorylation (S780, S807/S811, T826) that fully releases E2F. Genome-wide ChIP studies show RB1 occupies thousands of loci across promoters, enhancers, and CTCF-bound sites, and the same scaffolding activity supports several non-canonical functions that are well documented but mechanistically downstream of the E2F-repression core: repression of RNA polymerase III transcription (via TFIIIB binding), genome maintenance (interactions with Ku70/Ku80/XRCC5/XRCC6 in cNHEJ and with BRG1 in HR-coupled programs), heterochromatin/SAHF formation in cellular senescence, and lineage-specific transcriptional cooperation with non-E2F partners (RUNX2, AR, CEBPD, PU.1). RB1 is the mutated locus in hereditary retinoblastoma and is recurrently lost in many adult tumors; its functional state is a clinically actionable biomarker for CDK4/6 inhibitor response.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0031175 neuron projection development
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033. RB1 has documented roles in neuronal differentiation in vivo (e.g. murine Rb1 loss causes defects in retinal, cortical and CNS neuron development; the Rb/E2F axis regulates terminal differentiation in many neuronal lineages — deep research synthesis). However, neuron projection development is a tissue/cell-type-specific outcome of the broader Rb-E2F transcriptional repression program rather than a constitutive core RB1 function. The core RB1 function (Rb-E2F complex, G1/S transition repression, transcription coregulator activity, nucleoplasmic localization) is captured by other rows in this annotation set.
Reason: Tissue/cell-type-specific neuronal differentiation context rather than a core RB1 function. Canonical RB1 activity (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental and IPI evidence elsewhere in this file (PMID:7923370; PMID:16360038 IPI on GO:0035189). Mechanical IBA-PANTHER batch (batch 6 of #347).
GO:0048667 cell morphogenesis involved in neuron differentiation
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033. As with GO:0031175 above, RB1 contributes to terminal neuronal differentiation in specific developmental contexts via the Rb-E2F transcriptional program, but cell morphogenesis involved in neuron differentiation is a downstream tissue-specific consequence rather than a core RB1 molecular/cellular function.
Reason: Tissue/cell-type-specific neuronal differentiation context rather than a core RB1 function. Canonical RB1 activity (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental and IPI evidence elsewhere in this file (PMID:7923370; PMID:16360038 IPI on GO:0035189). Mechanical IBA-PANTHER batch (batch 6 of #347).
GO:0000785 chromatin
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for chromatin localization. Hypophosphorylated active RB1 is chromatin-bound at E2F target gene promoters and recruits chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) — this is a canonical, well-supported RB1 cellular localization (PMID:7923370; deep research synthesis). Chromatin binding is independently supported by direct experimental evidence elsewhere in this file.
Reason: Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; PMID:17540172 IDA rows on heterochromatin/chromatin lock complex) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IBA-PANTHER batch (batch 6 of #347).
GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding
IBA
GO_REF:0000033 		MODIFY
Summary: IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for sequence-specific DNA binding at Pol II regulatory regions. RB1 itself does not contain a sequence-specific DNA-binding domain; its occupancy of E2F target gene promoters (E2F sites in regulatory regions) is mediated indirectly by binding the activator E2F1/2/3 transcription factors (which contain the sequence-specific winged-helix DNA-binding domain) via the RB_A/RB_B pocket. The sequence specificity is therefore contributed by E2F1/2/3, not by RB1. The closely related GO:0001012 (RNA polymerase II transcription regulatory region DNA binding) — which does not require the annotated protein to contribute the sequence-specific interface — is the appropriate term for RB1's indirect, complex-mediated DNA occupancy.
Reason: Essence of the annotation (RB1 occupies Pol II regulatory regions via the Rb-E2F complex) is correct, but the "sequence-specific" qualifier of GO:0000977 does not apply to RB1: sequence specificity is contributed by E2F1/2/3 (winged-helix DNA-binding domain), while RB1 binds the E2F protein via the RB_A/RB_B pocket rather than DNA directly. Replace with GO:0001012 (RNA polymerase II transcription regulatory region DNA binding), which captures the regulatory-region occupancy without the sequence-specific binding claim. Mechanical IBA-PANTHER batch (batch 6 of #347); action adjusted in response to PR #490 review.
GO:0035189 Rb-E2F complex
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for the Rb-E2F complex. RB1 is the defining pocket-protein component of the Rb-E2F transcriptional repressor complex; the RB_A/RB_B pocket directly engages activator E2F1/2/3 transactivation domains and DP1/DP2 heterodimer partners to occupy E2F target gene promoters (PMID:7923370; deep research synthesis). Independently supported by IPI evidence (PMID:16360038) on this same GO:0035189 term elsewhere in this annotation set and by the parallel IEA Ensembl-Compara row ACCEPTed in PR #461.
Reason: Canonical RB1 function — Rb-E2F complex is the namesake of the RB1 mechanism. Well supported by direct IPI evidence (PMID:16360038) on this exact term elsewhere in this file and by the parallel IEA row ACCEPTed in PR #461. Mechanical IBA-PANTHER batch (batch 6 of #347).
GO:2000134 negative regulation of G1/S transition of mitotic cell cycle
IBA
GO_REF:0000033 		ACCEPT
Summary: IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for negative regulation of the G1/S transition. Hypophosphorylated RB1 sequesters activator E2F1/2/3 and prevents transcription of S-phase entry genes (CCNE1, CDC6, MCM2-7, etc.); CDK4/6-Cyclin D phosphorylation of RB1 inactivates this repression and licenses G1/S progression (PMID:7923370; deep research synthesis). This is one of the most canonical RB1 functions, central to its tumor-suppressor role.
Reason: Canonical RB1 tumor-suppressor function — restraint of the G1/S transition via E2F sequestration is one of the best-characterized RB1 activities. Well supported by direct experimental and Reactome TAS evidence elsewhere in this file (PMID:19149898 TAS rows on G1/S regulation; ACCEPTed in earlier batches). Mechanical IBA-PANTHER batch (batch 6 of #347).
GO:0005634 nucleus
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation propagated via UniProt-keyword/InterPro2GO (GO_REF:0000120) for nuclear localization. RB1 is a canonical nuclear protein; hypophosphorylated active RB1 occupies E2F-target gene promoters in the nucleoplasm and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis). Nuclear localization is also independently supported by IDA (PMID:1531329, PMID:20940255) and by 17 Reactome TAS rows on GO:0005654 nucleoplasm already ACCEPTed in PR #444.
Reason: Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: IEA annotation propagated via UniProt-keyword/InterPro2GO (GO_REF:0000120) for cytoplasmic localization. RB1 is canonically a nuclear protein (active hypophosphorylated RB1 occupies E2F-target promoters in the nucleoplasm), but cytoplasmic localization is a real conditional secondary state. UniProt P06400 CC SUBCELLULAR LOCATION records cytoplasmic localization "when hyperphosphorylated (By similarity)" (projected from mouse Rb1 P13405) and additionally notes that interaction with PKP3 (Plakophilin 3) may sequester RB1 to the cytoplasm (By similarity, from P13405). PMID:20940255 (Pickard et al. 2010) independently shows RB1 mislocalizes to the cytoplasm when not PCAF-acetylated during keratinocyte differentiation. None of these cytoplasmic contexts represent the canonical Rb-E2F transcriptional corepressor function captured by core_functions[0].
Reason: Cytoplasmic localization is a real but non-core secondary state — represents inactive/sequestered or apoptotic-context RB1, downstream of the defining nuclear Rb-E2F transcriptional corepressor activity already ACCEPTed (GO:0005634 nucleus IEA in batch 5; 17 Reactome TAS GO:0005654 nucleoplasm rows ACCEPTed in PR #444; PMID:20940255 EXP nuclear localization). Same precedent as the GO:0005819 spindle KEEP_AS_NON_CORE row in batch 15 (#551) — IEA localization counterpart to a non-core RB1 functional context.
GO:0006357 regulation of transcription by RNA polymerase II
IEA
GO_REF:0000002 		ACCEPT
Summary: IEA annotation propagated via InterPro2GO (GO_REF:0000002) for regulation of transcription by RNA polymerase II. RB1 is a chromatin-bound corepressor of Pol II transcription, primarily through binding and inhibition of activator E2F1/2/3 transcription factors at the RB_A/RB_B pocket and recruitment of chromatin-modifying complexes (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis). Pol II transcriptional regulation is also captured by GO:0000122 TAS (PMID:19149898) elsewhere in this file.
Reason: Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).
GO:0032502 developmental process
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: IEA annotation propagated via GO_REF:0000117 (electronic, ARBA/InterPro2GO-type) for the high-level grouping term developmental process. RB1 is a pleiotropic tumor suppressor whose non-canonical biology genuinely extends to promotion of differentiation across multiple lineages (myocytes, adipocytes, erythroid and neuronal precursors) and to senescence and lineage-fidelity maintenance (deep research synthesis: sanidas2024patternsinthe; huang2024therapeuticstrategiesfor; corroborated by PMID:9448006 discussion noting nonphosphorylated pRB promotes differentiation of myocytes, adipocytes, erythroid and neuronal cells). However, developmental process is an extremely broad grouping term and these developmental roles are downstream contexts of, not equivalent to, the defining Rb-E2F G1/S transcriptional corepressor activity captured by core_functions[0].
Reason: RB1's developmental roles are real and literature-supported but represent pleiotropic non-core contexts downstream of the defining Rb-E2F cell-cycle corepressor function (already ACCEPTed: GO:0051726 regulation of cell cycle, GO:0006357 regulation of transcription by Pol II, the GO:0045892 IDA rows, and the 17 Reactome nucleoplasm TAS rows). Same KEEP_AS_NON_CORE precedent as the GO:0005737 cytoplasm and GO:0005819 spindle (batch 15, #551) rows — a real but non-core IEA aspect retained on record rather than removed. The term is too high-level to be core; it is not wrong.
GO:0051726 regulation of cell cycle
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA annotation propagated via UniProt-keyword/InterPro2GO (GO_REF:0000120) for regulation of cell cycle. RB1 is the prototypical pocket-protein G1/S-checkpoint regulator; hypophosphorylated RB1 represses E2F-driven S-phase entry and is two-step inactivated by Cyclin D-CDK4/6 then Cyclin E-CDK2 phosphorylation (PMID:7923370; deep research synthesis). Cell-cycle regulation is also captured by GO:2000134 TAS (PMID:19149898) and multiple IDA/IMP rows elsewhere in this file.
Reason: Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).
GO:0005515 protein binding
IPI
PMID:10779361
Mutagenesis of the pRB pocket reveals that cell cycle arrest... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:10944455
RBP95, a novel leucine zipper protein, binds to the retinobl... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:11268000
Ebp1, an ErbB-3 binding protein, interacts with Rb and affec... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:12434308
Protein Phosphatase 1 binds strongly to the retinoblastoma p... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:12502741
Structural basis for the recognition of the E2F transactivat... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:12598654
Crystal structure of the retinoblastoma tumor suppressor pro... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:12743606
The adenovirus E1A oncoprotein recruits the cellular TRRAP/G... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:12813456
Interaction of the HPV E7 proteins with the pCAF acetyltrans... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:1331501
Homologous sequences in adenovirus E1A and human papillomavi... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:14555653
LEK1 is a potential inhibitor of pocket protein-mediated cel... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:14645241
Interactions between activating signal cointegrator-2 and th... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:15084261
Cyclin C/cdk3 promotes Rb-dependent G0 exit. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16061792
Association of the human papillomavirus type 16 E7 oncoprote... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16249186
Structure of the human Papillomavirus E7 oncoprotein and its... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16286473
The retinoblastoma family proteins bind to and activate diac... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16360038
Structure of the Rb C-terminal domain bound to E2F1-DP1: a m... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16374512
DNA-damage-responsive acetylation of pRb regulates binding t... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16510145
Effects of MdmX on Mdm2-mediated downregulation of pRB. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16616919
The arginine methyltransferase PRMT2 binds RB and regulates ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16763564
Roles for APIS and the 20S proteasome in adenovirus E1A-depe... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16766265
HMGA2 induces pituitary tumorigenesis by enhancing E2F1 acti... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:17045206
p53 family members in myogenic differentiation and rhabdomyo... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:17274640
A limited screen for protein interactions reveals new roles ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:17292836
Structure of the oncoprotein gankyrin in complex with S6 ATP... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:17349581
Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to in... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:17380128
Phosphorylation of pRB at Ser612 by Chk1/2 leads to a comple... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:17620057
Deacetylation of the retinoblastoma tumour suppressor protei... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:18391203
EBV-encoded EBNA-6 binds and targets MRS18-2 to the nucleus,... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:1870208
Purification and characterization of human papillomavirus ty... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:19017275
Shigella flexneri type III secretion system effectors OspB a... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:19249677
Proapoptotic function of the retinoblastoma tumor suppressor... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:19513100
Direct binding of pRb/E2F-2 to GATA-1 regulates maturation a... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:19651603
Structural basis for subversion of cellular control mechanis... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:20088881
Targeting mechanism of the retinoblastoma tumor suppressor b... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:20195357
A comprehensive resource of interacting protein regions for ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:20871633
p38 phosphorylates Rb on Ser567 by a novel, cell cycle-indep... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:21119616
Interplay between lysine methylation and Cdk phosphorylation... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:21139044
Rb-Raf-1 interaction disruptor RRD-251 induces apoptosis in ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:2138977
The regions of the retinoblastoma protein needed for binding... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:2153075
The region of the HPV E7 oncoprotein homologous to adenoviru... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:2162480
Definition of the minimal simian virus 40 large T antigen- a... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:2189724
Two distinct and frequently mutated regions of retinoblastom... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:21903422
Mapping a dynamic innate immunity protein interaction networ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:21952639
NIRF constitutes a nodal point in the cell cycle network and... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:22157815
The SNF2-like helicase HELLS mediates E2F3-dependent transcr... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:22301153
The coronavirus endoribonuclease Nsp15 interacts with retino... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:22366686
Senescence is an endogenous trigger for microRNA-directed tr... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:22615382
H3K4 demethylation by Jarid1a and Jarid1b contributes to ret... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:22773103
LEDGF (p75) promotes DNA-end resection and homologous recomb... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:22810586
Interpreting cancer genomes using systematic host network pe... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:22898364
Comparative analysis of virus-host interactomes with a mamma... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:23472054
The ING1a tumor suppressor regulates endocytosis to induce c... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:23602568
The protein interaction landscape of the human CMGC kinase g... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:23752268
The functional interactome landscape of the human histone de... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:23783631
Modulation of allostery by protein intrinsic disorder. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:23859194
Mitogen-activated protein kinase p38 and retinoblastoma prot... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:24823443
HAUSP, a novel deubiquitinase for Rb - MDM2 the critical reg... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:25609649
Proteomic analyses reveal distinct chromatin-associated and ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:25814554
Phospho-tyrosine dependent protein-protein interaction netwo... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:29521627
A compartmentalized signaling network mediates crossover con... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:29997244
LuTHy: a double-readout bioluminescence-based two-hybrid tec... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:32707033
Kinase Interaction Network Expands Functional and Disease Ro... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:34591612
A protein interaction landscape of breast cancer. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:34591642
A protein network map of head and neck cancer reveals PIK3CA... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:35140242
Human transcription factor protein interaction networks. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:39938803
Structural and functional analysis of cancer-associated miss... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:7592647
Association of human Pur alpha with the retinoblastoma prote... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:7664264
The nuclear tyrosine kinase Rak associates with the retinobl... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:7791904
Interaction between the retinoblastoma protein and the oncop... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:7890747
Binding of an interferon-inducible protein (p202) to the ret... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:7923370
The retinoblastoma protein and BRG1 form a complex and coope... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:8756624
Cyclin-binding motifs are essential for the function of p21C... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:9067421
A DNA polymerase alpha accessory protein exhibits structural... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:9468139
Retinoblastoma protein recruits histone deacetylase to repre... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:9468140
Retinoblastoma protein represses transcription by recruiting... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:9608663
The rubella virus putative replicase interacts with the reti... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:9697699
A retinoblastoma-binding protein that affects cell-cycle con... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:9881977
Direct suppression of Stat1 function during adenoviral infec... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0042802 identical protein binding
IPI
PMID:16360038
Structure of the Rb C-terminal domain bound to E2F1-DP1: a m... 		MARK AS OVER ANNOTATED
Summary: Rubin et al. 2005 (PMID:16360038, Cell) is the crystal structure of the Rb C-terminal domain (RbC) bound to the E2F1-DP1 heterodimer. It characterizes a high-affinity heterotypic interaction in which RbC contacts the marked-box domains of E2F1 and DP1, plus a phosphorylation-induced intramolecular RbC-pocket contact within a single RB1 molecule. It does not demonstrate RB1 homodimerization or RB1-RB1 self-association, and RB1 is not characterized as a homodimer in its core E2F-repression / chromatin-scaffolding biology. GO:0042802 identical protein binding implies an RB1-RB1 interaction that this paper does not support. The informative interactions from this structure are already captured by the batch-17 ACCEPT rows GO:0035189 (Rb-E2F complex) and GO:0060090 (molecular adaptor activity).
Reason: The cited Rubin 2005 structure characterizes heterotypic RbC-E2F1-DP1 binding, not RB1 self-association; identical protein binding is an unsupported, uninformative generic binding term for this evidence. Conservative demotion consistent with the GO:0005515 precedent in this same review and the batch-17 handling of PMID:16360038. A second independent GO:0042802 row (PMID:8288605) remains PENDING and is deferred to a later batch.
GO:0042802 identical protein binding
IPI
PMID:8288605
Identification of discrete structural domains in the retinob... 		KEEP AS NON CORE
Summary: IPI annotation for identical protein binding sourced from Hensey et al. 1994 (PMID:8288605). This study expressed and purified recombinant full-length human p110RB and an N-terminally truncated p56RB, and used non-denaturing PAGE, electron microscopy and yeast two-hybrid analysis to show that full-length RB1 self-associates into oligomeric/higher-order structures via interactions between its amino- and carboxy-terminal domains, a property absent from the N-terminally truncated form. This is genuine, specific evidence for RB1 homo-oligomerization (identical protein binding), distinct from the heterotypic RbC-E2F1-DP1 contacts cited for the other GO:0042802 row (PMID:16360038) that was demoted because that source did not characterize self-association.
Reason: RB1 self-oligomerization is a real, specifically-evidenced biochemical property (yeast two-hybrid + native PAGE + EM in PMID:8288605), so the term is correctly supported here and is informative rather than generic protein binding. However it is a secondary structural property, not the defining E2F-pocket corepressor / chromatin-scaffold activity captured by core_functions[0] (GO:0003714); kept on record at non-core priority. This resolves the GO:0042802 (PMID:8288605) row explicitly deferred by the batch-17 handling of the PMID:16360038 counterpart. Mechanical binding-partner-MF batch (batch 22 of #347).
GO:0002062 chondrocyte differentiation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Tissue-specific differentiation phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): Rb1 is required for chondrocyte differentiation and endochondral ossification in conditional-knockout mouse skeletal models, but this is a downstream lineage-specific consequence of RB1's core E2F-repression / chromatin-scaffolding activity (e.g. partnering with RUNX2 in cartilage/bone progenitors) rather than a primary RB1 molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0003180 aortic valve morphogenesis
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Tissue-specific developmental phenotype projected from mouse Rb1 ortholog: Rb1-null mouse hearts exhibit cardiac valve defects, but this is a downstream developmental consequence of Rb1's core role in E2F-mediated proliferation/differentiation control in cardiac neural crest and valvular interstitial cells, not a primary RB1 molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0005667 transcription regulator complex
IEA
GO_REF:0000107 		ACCEPT
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for transcription regulator complex. RB1 is the defining component of the Rb-E2F transcriptional repressor complex and broadly participates in chromatin-bound transcription regulator assemblies with HDAC1, SUV39H1, BRG1/SMARCA4, and lineage-specific TFs (PMID:7923370; deep research synthesis). Independently supported by the more specific GO:0035189 Rb-E2F complex IPI rows in this file.
Reason: Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).
GO:0005819 spindle
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for spindle localization. RB1 has a documented but non-core mitotic-fidelity role at the centromere/condensin II axis (CAP-D3 mislocalization, merotelic attachment, lagging chromosomes) shown by Manning et al. 2010 PMID:20551165 — this is the same mitotic-fidelity biology that motivates spindle-adjacent localization, but it is downstream of, and tangential to, RB1's defining function as the Rb-E2F transcriptional corepressor that enforces the G1/S restriction point.
Reason: RB1's contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1's primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Spindle IEA projected from mouse Rb1 ortholog (GO_REF:0000107) is the localization counterpart to the PMID:20551165 mitotic-fidelity IMP cluster already KEEP_AS_NON_CORE in batch 11 of #347.
GO:0006915 apoptotic process
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Downstream phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): Rb1 loss sensitises cells to apoptosis through deregulated E2F1-driven proapoptotic gene programs (e.g. p73, BIM, APAF1) and altered Bcl-2-family balance, but apoptotic engagement is a context-dependent consequence of RB1's core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 molecular function. Consistent with the existing KEEP_AS_NON_CORE treatment of GO:2001234 negative regulation of apoptotic signaling pathway (ISS PMID:24027266) elsewhere in this file.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0007283 spermatogenesis
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Tissue-specific developmental phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): germ-cell-conditional Rb1 deletion in the mouse compromises spermatogonial / Sertoli-cell programs and male fertility, but spermatogenesis is a downstream lineage-specific consequence of RB1's core E2F-repression / chromatin-scaffolding role in proliferating progenitors rather than a primary RB1 molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0019899 enzyme binding
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for enzyme binding. GO:0019899 is an uninformative generic MF parent term that captures the broad class of RB1's enzymatic-partner interactions without naming what RB1 actually does mechanistically. RB1's informative enzyme-binding biology is already captured at higher specificity by the chromatin-modifying enzyme interactions ACCEPTed in this file (HDAC1, SUV39H1, BRG1/SMARCA4 corepressor recruitment via the RB_A/RB_B pocket; PMID:7923370 RB-BRG1 cooperation; deep research synthesis) and by the GO:0001047 / GO:0003682 chromatin-binding rows. Per CLAUDE.md curation guidelines, generic adapter/binding parent terms should be demoted in favor of more specific MF annotations.
Reason: Generic enzyme binding is uninformative for RB1's well-characterized adapter/scaffolding biology with chromatin-modifying enzymes (HDAC1, SUV39H1, BRG1/SMARCA4) and cell-cycle kinases (CDK4/CDK6 phosphorylation of RB1). Same precedent as the uniform demotion of generic GO:0005515 protein binding IPI rows in this file (50+ rows ACCEPTed as MARK_AS_OVER_ANNOTATED per BAG3 #313 / KRAS #349 / BCAP31 PR #317 / RB1 PR #430 precedent).
GO:0030308 negative regulation of cell growth
IEA
GO_REF:0000107 		ACCEPT
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for negative regulation of cell growth. RB1 is the prototypical pocket-protein antiproliferative tumor suppressor: hypophosphorylated RB1 binds activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, masks their transactivation domains, recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) and durably represses S-phase gene transcription, thereby restricting net cellular growth and proliferation (PMID:7923370; deep research synthesis). Already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9 and the GO:0051726 regulation of cell cycle IEA row ACCEPTed in batch 5.
Reason: Canonical RB1 antiproliferative function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 14 of #347).
GO:0032869 cellular response to insulin stimulus
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Tissue-specific metabolic phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): Rb1 modulates insulin sensitivity in adipocytes and beta cells through E2F-mediated control of metabolic / differentiation gene programs (paralleling the existing GO:0120163 cold-induced thermogenesis ISS row at line 1296), but insulin-stimulus response is a context-dependent metabolic consequence of RB1's core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0035189 Rb-E2F complex
IEA
GO_REF:0000107 		ACCEPT
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for Rb-E2F complex. RB1 is the defining pocket-protein component of the Rb-E2F transcriptional repressor complex; the RB_A/RB_B pocket directly engages activator E2F1/2/3 transactivation domains and DP heterodimer partners to occupy E2F target gene promoters (PMID:7923370; deep research synthesis). Independently supported by IPI evidence (PMID:16360038) on this exact term elsewhere in this file.
Reason: Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).
GO:0045786 negative regulation of cell cycle
IEA
GO_REF:0000107 		ACCEPT
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for negative regulation of cell cycle. Negative regulation of cell-cycle progression is the defining RB1 tumor-suppressor activity: hypophosphorylated RB1 sequesters activator E2Fs and represses S-phase genes at the G1 restriction point until it is sequentially inactivated by Cyclin D-CDK4/6 and Cyclin E-CDK2 phosphorylation (PMID:7923370; deep research synthesis). Already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9 and the GO:0051726 regulation of cell cycle IEA row ACCEPTed in batch 5.
Reason: Canonical RB1 cell-cycle-restriction function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 14 of #347).
GO:0050728 negative regulation of inflammatory response
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 loss can increase tissue inflammation as part of the senescence-associated secretory phenotype (SASP) and altered chromatin programs, but inflammatory regulation is a contextual consequence of RB1's core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
IEA
GO_REF:0000107 		ACCEPT
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for RNA polymerase II-specific DNA-binding transcription factor binding. RB1 directly binds the E2F1/2/3 activator transcription factors (sequence-specific Pol II TFs) via its RB_A/RB_B pocket; this is the canonical RB1 molecular function (PMID:7923370; deep research synthesis). Independently supported by IPI evidence on the related Rb-E2F complex (GO:0035189) and by core_functions[0] in this file.
Reason: Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).
GO:0120163 negative regulation of cold-induced thermogenesis
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Tissue-specific phenotype projected from mouse Rb1: Rb1 represses brown-adipocyte / thermogenic gene programs (Ucp1) in white adipose tissue (PMID:19417128), but cold-induced thermogenesis is a downstream metabolic consequence of RB1's role in adipocyte differentiation/transcription control rather than a core RB1 function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0140297 DNA-binding transcription factor binding
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for DNA-binding transcription factor binding. RB1 binds multiple sequence-specific DNA-binding transcription factors — most prominently activator E2F1/2/3 via the RB_A/RB_B pocket, and lineage-specific TFs (RUNX2, AR, CEBPD, PU.1) in differentiation contexts (PMID:7923370; deep research synthesis). Same canonical function captured more specifically by GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding) which is also ACCEPTed in this file, and all of RB1's characterised TF-binding partners (E2F1/2/3, RUNX2, AR, CEBPD, PU.1) are Pol II-specific TFs, so the parent adds no additional biological information beyond what the child captures.
Reason: Parent term of GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), which is ACCEPTed in this same batch and captures the full scope of RB1's TF-binding biology — every characterised RB1 partner (E2F1/2/3, RUNX2, AR, CEBPD, PU.1) is a Pol II-specific TF, so the more general GO:0140297 is not entirely wrong but represents an over-annotation per the schema definition.
GO:1903055 positive regulation of extracellular matrix organization
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 modulates ECM organization through transcriptional control of stromal/fibroblast programs, but ECM organization is a contextual consequence of RB1's core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:1903944 negative regulation of hepatocyte apoptotic process
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Tissue-specific phenotype projected from mouse Rb1 ortholog: Rb1 modulates hepatocyte apoptosis sensitivity in liver-specific contexts, but this is a downstream tissue-level consequence of RB1's core E2F / cell-cycle / chromatin role rather than a primary molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:1904028 positive regulation of collagen fibril organization
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 affects collagen-fibril organization via transcriptional regulation of stromal programs, but collagen-fibril organization is a contextual consequence of RB1's core role in cell-cycle / differentiation control rather than a primary molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:1904761 negative regulation of myofibroblast differentiation
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Tissue-specific phenotype projected from mouse Rb1 ortholog: Rb1 restricts myofibroblast differentiation programs in fibrotic contexts, but this is a downstream cell-fate consequence of RB1's core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:2001234 negative regulation of apoptotic signaling pathway
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Downstream phenotype projected from mouse Rb1 ortholog: Rb1 affects apoptotic signaling sensitivity through E2F-target regulation (e.g. via BCL-2 family genes and cell-cycle/apoptosis crosstalk), but apoptotic-pathway regulation is a context-dependent consequence of RB1's core E2F-repression / chromatin-scaffolding role rather than a primary RB1 function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0005634 nucleus
IDA
PMID:17540172
L3MBTL1, a histone-methylation-dependent chromatin lock. 		ACCEPT
Summary: IDA annotation for nuclear localization sourced from the chromatin lock complex paper (Trojer et al. 2007 Cell, PMID:17540172). RB1 was co-purified with L3MBTL1, core histones, histone H1b, and HP1gamma as a chromatin-bound nuclear complex that compacts facultative heterochromatin. Nuclear localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444) and by IEA propagations ACCEPTed in PR #461.
Reason: Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444) and by the L3MBTL1 chromatin-lock complex co-purification reported in PMID:17540172. Mechanical PMID:17540172-cluster batch (batch 7 of #347).
GO:0031507 heterochromatin formation
IDA
PMID:17540172
L3MBTL1, a histone-methylation-dependent chromatin lock. 		ACCEPT
Summary: IDA annotation from the L3MBTL1 chromatin lock complex paper (Trojer et al. 2007 Cell, PMID:17540172). The L3MBTL1 MBT domains, in a complex with RB1, core histones, histone H1b, and HP1gamma, compact nucleosomal arrays dependent on mono- and dimethylation of histone H4 lysine 20 and histone H1b lysine 26 — the defining biochemistry of facultative heterochromatin formation. RB1 participates in this chromatin-compaction activity as a stoichiometric complex member.
Reason: Canonical RB1 function, directly supported by IDA evidence in PMID:17540172 showing RB1 in the L3MBTL1 chromatin lock complex that compacts nucleosomal arrays into facultative heterochromatin. Consistent with RB1's broader role in chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) captured in core_functions[0]. Mechanical PMID:17540172-cluster batch (batch 7 of #347).
GO:0045892 negative regulation of DNA-templated transcription
IMP
PMID:17540172
L3MBTL1, a histone-methylation-dependent chromatin lock. 		ACCEPT
Summary: IMP annotation from the L3MBTL1 chromatin lock complex paper (Trojer et al. 2007 Cell, PMID:17540172). L3MBTL1, in a complex with RB1, was shown to negatively regulate the expression of a subset of genes regulated by E2F — directly linking the chromatin-lock biochemistry to repression of RB-E2F target genes. This is a canonical RB1 transcriptional repressor function delivered via chromatin compaction rather than only via E2F transactivation-domain masking.
Reason: Canonical RB1 function, well supported by IMP evidence in PMID:17540172 (L3MBTL1+RB1 chromatin lock represses a subset of E2F target genes) and consistent with the broader RB-E2F repressor mechanism captured in core_functions[0]. Mechanical PMID:17540172-cluster batch (batch 7 of #347).
GO:0061793 chromatin lock complex
IPI
PMID:17540172
L3MBTL1, a histone-methylation-dependent chromatin lock. 		ACCEPT
Summary: IPI annotation from the namesake paper (Trojer et al. 2007 Cell, PMID:17540172) — RB1 co-purifies with L3MBTL1, core histones, histone H1b, and HP1gamma as the chromatin lock complex. GO:0061793 chromatin lock complex was defined for this exact biochemistry. RB1 is a stoichiometric component of this complex and contributes the E2F-target-gene specificity that links the L3MBTL1 H4K20me1/2-reading chromatin-compaction activity to RB1-controlled promoter sets.
Reason: RB1 is a defining stoichiometric component of the chromatin lock complex per the namesake paper (PMID:17540172, IPI partner = L3MBTL1; cross-supports the same paper's IDA/IMP entries for GO:0031507 heterochromatin formation and GO:0045892 negative regulation of DNA-templated transcription already in this batch). Mechanical PMID:17540172-cluster batch (batch 7 of #347).
GO:0005654 nucleoplasm
IDA
GO_REF:0000052 		ACCEPT
Summary: IDA annotation for nucleoplasmic localization sourced from the Human Protein Atlas immunofluorescence curation (GO_REF:0000052). RB1 is a canonical nuclear/nucleoplasmic protein; hypophosphorylated active RB1 occupies E2F-target gene promoters in the nucleoplasm and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis). Nucleoplasmic localization is also independently supported by 17 Reactome TAS rows on GO:0005654 already ACCEPTed in PR #444 and by IEA propagations ACCEPTed in PR #461.
Reason: Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444) and by HPA immunofluorescence curation (GO_REF:0000052). Mechanical canonical-nuclear-localization batch (batch 10 of #347).
GO:0005634 nucleus
IDA
PMID:1531329
The interaction of RB with E2F coincides with an inhibition ... 		ACCEPT
Summary: IDA annotation for nuclear localization sourced from the RB-E2F interaction paper (Hiebert et al. 1992 Genes Dev, PMID:1531329). The paper demonstrates that RB1 interacts with E2F in a complex that inhibits E2F transcriptional activity, with the in vivo biochemistry performed on nuclear extracts. Nuclear localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444), by IEA propagations ACCEPTed in PR #461, and by the IDA nucleoplasm row from PMID:17540172 ACCEPTed in PR #499.
Reason: Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444). The Hiebert et al. 1992 paper is the canonical RB-E2F interaction paper and directly supports nuclear localization of RB1. Mechanical canonical-nuclear-localization batch (batch 10 of #347).
GO:0006355 regulation of DNA-templated transcription
IDA
PMID:1531329
The interaction of RB with E2F coincides with an inhibition ... 		MODIFY
Summary: IDA annotation from Hiebert et al. 1992 (PMID:1531329, "The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F"), a canonical RB-E2F repression paper. Transfection assays of the adenovirus E2 promoter show that "formation of the complex containing pRB and E2F coincides with an inhibition of E2F-dependent transcriptional activity" and that "a mutant pRB protein that does not associate with E2F does not inhibit transcription." This directly demonstrates that RB1 *negatively* (not merely "regulates") regulates DNA-templated transcription. The generic parent GO:0006355 is too broad for this directional finding; the specific child GO:0045892 (negative regulation of DNA-templated transcription) is exactly what is shown, is already captured in core_functions[0].directly_involved_in, and is concordantly supported by IDA/TAS rows elsewhere in this file (PMID:12065415, PMID:10783144, PMID:19223331, PMID:19149898).
Reason: Essence of the annotation (RB1 represses transcription via the Rb-E2F complex) is correct and canonical, but GO:0006355 is too general for the directional repressor activity that PMID:1531329 directly demonstrates. Replace with GO:0045892 (negative regulation of DNA-templated transcription), the specific term already present in core_functions[0]. Mechanical transcription-regulation batch (batch 20 of #347).
GO:0035189 Rb-E2F complex
IPI
PMID:16360038
Structure of the Rb C-terminal domain bound to E2F1-DP1: a m... 		ACCEPT
Summary: IPI annotation for the Rb-E2F complex sourced from Rubin et al. 2005 (PMID:16360038, Cell), the landmark crystal structure of the Rb C-terminal domain (RbC) bound to the E2F1-DP1 heterodimer. The paper demonstrates a high-affinity RbC-E2F-DP interaction shared by all Rb and E2F family members and resolves an intertwined heterodimer in which the marked box domains of both E2F1 and DP1 contact RbC. This is direct structural evidence for the namesake Rb-E2F complex — the defining RB1 assembly already captured by core_functions[0] (in_complex: GO:0035189) and independently supported by the IBA GO:0035189 row ACCEPTed in batch 6 (which cites this same PMID:16360038 as its IPI anchor) and the parallel IEA Ensembl-Compara row ACCEPTed in PR #461.
Reason: Canonical RB1 function — the Rb-E2F complex is the namesake of the RB1 mechanism and is directly demonstrated at atomic resolution by PMID:16360038 (Rubin et al. 2005 RbC-E2F1-DP1 crystal structure). Reinforces core_functions[0] (in_complex: GO:0035189) and is consistent with the IBA GO:0035189 row already ACCEPTed in batch 6 and the IEA row ACCEPTed in PR #461. PMID:16360038 (Rubin et al. 2005) canonical RB-E2F structural batch (batch 17 of #347).
GO:0005634 nucleus
EXP
PMID:20940255
Acetylation of Rb by PCAF is required for nuclear localizati... 		ACCEPT
Summary: EXP annotation for nuclear localization sourced from Pickard et al. 2010 (PMID:20940255), "Acetylation of Rb by PCAF is required for nuclear localization and keratinocyte differentiation." The paper directly characterizes RB1 nuclear localization and shows that PCAF-mediated acetylation of Rb is required for its retention in the nucleus during keratinocyte differentiation. Nuclear localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444) and by IEA propagations ACCEPTed in PR #461.
Reason: Canonical RB1 localization, directly characterized by the cited paper (PMID:20940255) — RB1 nuclear localization is the explicit subject of the Pickard et al. 2010 study. Also independently supported by 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444 and by canonical IEA propagations. Mechanical canonical-nuclear-localization batch (batch 10 of #347).
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: ISS annotation projected from mouse Rb1 (UniProtKB:P13405) via GO_REF:0000024 for cytoplasmic localization. Same biology as the parallel IEA GO_REF:0000120 cytoplasm row in this file: cytoplasmic localization is a real but conditional secondary state. UniProt P06400 CC SUBCELLULAR LOCATION records cytoplasmic localization "when hyperphosphorylated (By similarity)" plus PKP3 (Plakophilin 3) interaction-mediated sequestration (both By similarity from P13405); PMID:20940255 independently shows RB1 mislocalizes to the cytoplasm when not PCAF-acetylated during keratinocyte differentiation. Not the canonical Rb-E2F nuclear corepressor function captured by core_functions[0].
Reason: Cytoplasmic localization is a real but non-core secondary state — represents inactive/sequestered or apoptotic-context RB1, downstream of the defining nuclear Rb-E2F transcriptional corepressor activity already ACCEPTed (GO:0005634 nucleus IEA in batch 5; 17 Reactome TAS GO:0005654 nucleoplasm rows ACCEPTed in PR #444; PMID:20940255 EXP nuclear localization). Same precedent as the GO:0005819 spindle KEEP_AS_NON_CORE row in batch 15 (#551). Resolves both PENDING cytoplasm rows (IEA + ISS) in a single batch since they describe identical biology from parallel propagation routes.
GO:0000122 negative regulation of transcription by RNA polymerase II
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews hypophosphorylated pRb as a Pol II transcriptional corepressor that silences E2F-target S-phase genes via the RB-E2F repressor complex (and recruits chromatin-modifying partners HDAC1, BRM, BRG1/SMARCA4). Negative regulation of Pol II transcription is a canonical core RB1 activity; already ACCEPTed elsewhere in this file via IEA (GO_REF:0000107) and supported by IDA evidence on PMID:7923370 and PMID:1531329.
Reason: Negative regulation of Pol II transcription is one of the best-characterized RB1 activities and is consistent with the existing core_functions[0] block (E2F repression at S-phase promoters). PMID:19149898 explicitly describes pRb as forming "active pRb-E2F transcriptional repressor complexes that silence genes required for S-phase entry." Mechanical TAS batch (batch 9 of #347) — all 8 PMID:19149898 TAS rows describe canonical RB1 repressor/cell-cycle functions and are uniformly ACCEPTed in this batch.
GO:2000134 negative regulation of G1/S transition of mitotic cell cycle
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews the prototypical RB1 function at the G1/S restriction point — hypophosphorylated pRb sequesters E2F1/2/3 and prevents S-phase entry until inactivated by Cyclin D-CDK4/6 and Cyclin E-CDK2 phosphorylation. Negative regulation of G1/S is a canonical core RB1 activity, already captured elsewhere in this file via IBA (PR #490, GO_REF:0000033) and IEA propagation.
Reason: Negative regulation of the G1/S transition is the defining RB1 tumor-suppressor activity, central to the existing core_functions[0] block. PMID:19149898 directly describes the CDK4/6/Cyclin D - pRb - E2F switch at the G1/S restriction point. Mechanical TAS batch (batch 9 of #347).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-188386 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-188390 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-69227 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0051276 chromosome organization
IMP
PMID:20551165
Loss of pRB causes centromere dysfunction and chromosomal in... 		KEEP AS NON CORE
Summary: IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB depletion compromises centromeric localization of CAP-D3/condensin II and chromosome cohesion, leading to merotelic attachment and chromosome missegregation. Real RB1 biology — RB1 loss undermines mitotic fidelity via condensin II / centromere effects — but this is a non-cell-cycle-arrest mitotic phenotype that is downstream of, and tangential to, RB1's defining function as the Rb-E2F transcriptional corepressor that enforces the G1/S restriction point. The Manning study explicitly frames this as separate from RB1's "best-known regulation of the G1/S-phase transition."
Reason: RB1's contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1's primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.
GO:0060090 molecular adaptor activity
EXP
PMID:16360038
Structure of the Rb C-terminal domain bound to E2F1-DP1: a m... 		ACCEPT
Summary: EXP annotation for molecular adaptor activity sourced from Rubin et al. 2005 (PMID:16360038, Cell). The crystal structure of RbC bound to E2F1-DP1 shows RbC forming an intertwined heterodimer that simultaneously contacts the marked box domains of both E2F1 and DP1, while the Rb pocket independently engages the E2F transactivation domain. RB1 thereby acts as a molecular adaptor/scaffold that bridges the activator E2F-DP heterodimer to the pocket and, in the cellular context, to recruited chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) — the bridging architecture underpinning core_functions[0] (masking E2F transactivation domains and recruiting chromatin corepressors). Per CLAUDE.md curation guidelines, this informative adaptor MF term is preferred over the generic GO:0005515 protein binding rows uniformly demoted elsewhere in this file.
Reason: Canonical RB1 scaffolding/adaptor molecular function, demonstrated by direct experimental (EXP) structural evidence in PMID:16360038 (Rubin et al. 2005): RbC simultaneously bridges the E2F1 and DP1 marked box domains, the structural basis for RB1 tethering activator E2F-DP heterodimers to the pocket and to recruited chromatin corepressors. Informative MF term preferred over generic protein binding per CLAUDE.md, and consistent with the bridging mechanism described in core_functions[0]. PMID:16360038 (Rubin et al. 2005) canonical RB-E2F structural batch (batch 17 of #347).
GO:0140297 DNA-binding transcription factor binding
IPI
PMID:19223331
HMGB1 and HMGB2 proteins up-regulate cellular expression of ... 		MARK AS OVER ANNOTATED
Summary: IPI annotation for DNA-binding transcription factor binding citing Stros et al. 2009 (PMID:19223331). In this study, GST pull-down and co-immunoprecipitation demonstrate a direct physical pRb-HMGB1 interaction, and ectopic pRb suppresses HMGB1/HMGB2-driven transactivation of the topo IIalpha (TOP2A) promoter by modulating NF-Y occupancy. RB1 binding DNA-binding transcription factors is a genuine RB1 molecular activity (canonically activator E2F1/2/3 via the RB_A/RB_B pocket, plus lineage-specific TFs), but the same biology is captured more specifically by GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), already ACCEPTed in this file, since every characterised RB1 TF partner (E2F1/2/3, RUNX2, AR, CEBPD, PU.1; and the Pol II-context HMGB1/NF-Y axis here) is Pol II-specific.
Reason: Consistent with the established in-file decision on the GO:0140297 IEA row (GO_REF:0000107): GO:0140297 is the over-general parent of GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), which is ACCEPTed and captures the full scope of RB1's TF-binding biology. The parent adds no biological information beyond the ACCEPTed child, so the term is not wrong but represents an over-annotation. The PMID:19223331 pRb-HMGB1 interaction is a Pol II transcription-context interaction already covered by the child term. Mechanical binding-partner-MF batch (batch 22 of #347).
GO:0003714 transcription corepressor activity
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes hypophosphorylated pRb as a transcriptional corepressor that represses E2F-target promoters via chromatin remodeling — including direct interactions with HDAC1, BRM, and the SWI/SNF catalytic subunit BRG1/SMARCA4. Transcription corepressor activity is a canonical RB1 MF activity already supported by IDA evidence elsewhere in this file.
Reason: Transcription corepressor activity is one of the defining biochemical activities of RB1 at E2F-target promoters and is consistent with the existing core_functions[0] block. PMID:19149898 explicitly frames pRb as forming "transcriptional repressor complexes that silence genes required for S-phase entry." Mechanical TAS batch (batch 9 of #347).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9659782 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-113503 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-187948 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9687377 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9851127 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005634 nucleus
TAS
PMID:3657987
The retinoblastoma susceptibility gene encodes a nuclear pho... 		ACCEPT
Summary: TAS annotation for nuclear localization sourced from Lee et al. 1987 Nature (PMID:3657987), the foundational paper that identified the retinoblastoma gene product as a nuclear phosphoprotein. The paper explicitly states that "biochemical fractionation and immunofluorescence studies demonstrate that the majority of the protein is located within the nucleus." This is the original characterization of RB1 as a nuclear protein and is independently corroborated by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444), IDA evidence (PMID:17540172 in PR #499, PMID:1531329, PMID:20940255 in this batch), and canonical IEA propagations ACCEPTed in PR #461.
Reason: Canonical RB1 localization established in the foundational Lee et al. 1987 Nature paper (PMID:3657987), which directly demonstrates nuclear localization by both biochemical fractionation and immunofluorescence. Nuclear localization is one of the defining features of RB1 from the moment the gene was cloned. Mechanical canonical-nuclear-localization batch (batch 10 of #347).
GO:0030308 negative regulation of cell growth
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS annotation projected via UniProt/InterPro template (GO_REF:0000024) for negative regulation of cell growth, based on conservation of the RB pocket domain. RB1 is the prototypical pocket-protein antiproliferative tumor suppressor: hypophosphorylated RB1 binds activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket and represses S-phase gene transcription, restricting net cellular growth and proliferation (PMID:7923370; deep research synthesis). Already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9.
Reason: Canonical RB1 antiproliferative function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical ISS-canonical batch (batch 14 of #347).
GO:0005829 cytosol
TAS
Reactome:R-HSA-9660615 		KEEP AS NON CORE
Summary: TAS annotation for cytosolic localization sourced from a Reactome disease event ('Defective RB1 does not translocate to the nucleus') describing loss-of-function RB1 nonsense/frameshift/NLS-deletion mutants (e.g. RB1 R830_G887 / delEx24-25) that lack the bipartite C-terminal NLS (residues 860-876) and are retained in the cytosol (PMID:8413247 Zacksenhaus et al. 1993; PMID:9326330 Bremner et al. 1997). Wild-type RB1 is a nuclear chromatin-bound corepressor; cytosolic retention is restricted to NLS-loss tumor mutants and is therefore a pathological mislocalization rather than a constitutive cellular compartment for the wild-type protein.
Reason: Real biology in a disease/mutant context (NLS-loss RB1 cancer mutants retained in the cytosol) but not a core wild-type RB1 localization. RB1's core compartment is the nucleus / nucleoplasm, where it carries out E2F repression and chromatin scaffolding (already ACCEPTed via the 17 R-HSA nucleoplasm TAS rows). Keeping on record at non-core priority is consistent with the analogous treatment of disease/ortholog-projected rows already in this file (e.g. PMID:24027266 GO:2001234 apoptosis row at line 1287 and PMID:19417128 GO:0120163 thermogenesis row at line 1296).
GO:0005829 cytosol
TAS
Reactome:R-HSA-9659820 		KEEP AS NON CORE
Summary: TAS annotation for cytosolic localization sourced from the Reactome event 'RB1 translocates to the nucleus', which describes the bipartite C-terminal NLS-dependent (residues 860-876) translocation of RB1 from the cytosol to the nucleus (PMID:8413247 Zacksenhaus et al. 1993). In the absence of the NLS only a small portion of RB1 reaches the nucleus while a large portion is retained in the cytosol. Cytosolic localization is therefore a transient pre-import state and an NLS-loss-mutant pathological state, not the steady-state compartment for the active wild-type protein.
Reason: Real biology in a disease/mutant context (NLS-loss RB1 cancer mutants retained in the cytosol) but not a core wild-type RB1 localization. RB1's core compartment is the nucleus / nucleoplasm, where it carries out E2F repression and chromatin scaffolding (already ACCEPTed via the 17 R-HSA nucleoplasm TAS rows). Keeping on record at non-core priority is consistent with the analogous treatment of disease/ortholog-projected rows already in this file (e.g. PMID:24027266 GO:2001234 apoptosis row at line 1287 and PMID:19417128 GO:0120163 thermogenesis row at line 1296).
GO:0005829 cytosol
TAS
Reactome:R-HSA-9682712 		KEEP AS NON CORE
Summary: TAS annotation for cytosolic localization sourced from the Reactome event 'nsp15 binds RB1', which describes SARS-CoV-1 non-structural protein 15 (nsp15) binding RB1 via its LXCXE/D motif and retaining RB1 in the cytosol (PMID:22301140 Bhardwaj et al. 2012). This is a viral-hijack mislocalization context — wild-type RB1 in uninfected cells is a chromatin-bound nuclear corepressor; cytosolic retention here is driven by viral nsp15 sequestration rather than reflecting a constitutive RB1 compartment.
Reason: Real biology in a disease/infection context (SARS-CoV-1 nsp15 sequesters wild-type RB1 in the cytosol via LXCXE/D-motif binding) but not a core wild-type RB1 localization in uninfected cells. RB1's core compartment is the nucleus / nucleoplasm, where it carries out E2F repression and chromatin scaffolding (already ACCEPTed via the 17 R-HSA nucleoplasm TAS rows). Keeping on record at non-core priority is consistent with the analogous treatment of disease/ortholog-projected rows already in this file (e.g. PMID:24027266 GO:2001234 apoptosis row at line 1287 and PMID:19417128 GO:0120163 thermogenesis row at line 1296).
GO:0045786 negative regulation of cell cycle
ISS
PMID:24027266
MiR-26b, upregulated in Alzheimer's disease, activates cell ... 		ACCEPT
Summary: ISS annotation citing PMID:24027266 (MiR-26b in Alzheimer's disease — miR-26b directly represses RB1 to drive cell-cycle re-entry in postmitotic neurons). The source paper's mechanism establishes RB1 as the canonical brake on cell-cycle progression: loss of RB1 via miR-26b targeting is sufficient to license aberrant cell-cycle re-entry. Negative regulation of cell cycle is the defining RB1 tumor-suppressor activity (PMID:7923370; deep research synthesis), already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9 and the GO:0051726 regulation of cell cycle IEA row ACCEPTed in batch 5.
Reason: Canonical RB1 cell-cycle-restriction function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical ISS-canonical batch (batch 14 of #347).
GO:2001234 negative regulation of apoptotic signaling pathway
ISS
PMID:24027266
MiR-26b, upregulated in Alzheimer's disease, activates cell ... 		KEEP AS NON CORE
Summary: Downstream phenotype projected from mouse Rb1 ortholog: Rb1 affects apoptotic signaling sensitivity through E2F-target regulation (e.g. via BCL-2 family genes and cell-cycle/apoptosis crosstalk), but apoptotic-pathway regulation is a context-dependent consequence of RB1's core E2F-repression / chromatin-scaffolding role rather than a primary RB1 function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0120163 negative regulation of cold-induced thermogenesis
ISS
PMID:19417128
Haploinsufficiency of the retinoblastoma protein gene reduce... 		KEEP AS NON CORE
Summary: Tissue-specific phenotype projected from mouse Rb1: Rb1 represses brown-adipocyte / thermogenic gene programs (Ucp1) in white adipose tissue (PMID:19417128), but cold-induced thermogenesis is a downstream metabolic consequence of RB1's role in adipocyte differentiation/transcription control rather than a core RB1 function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0003180 aortic valve morphogenesis
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Tissue-specific developmental phenotype projected from mouse Rb1 ortholog: Rb1-null mouse hearts exhibit cardiac valve defects, but this is a downstream developmental consequence of Rb1's core role in E2F-mediated proliferation/differentiation control in cardiac neural crest and valvular interstitial cells, not a primary RB1 molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0050728 negative regulation of inflammatory response
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 loss can increase tissue inflammation as part of the senescence-associated secretory phenotype (SASP) and altered chromatin programs, but inflammatory regulation is a contextual consequence of RB1's core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:1903055 positive regulation of extracellular matrix organization
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 modulates ECM organization through transcriptional control of stromal/fibroblast programs, but ECM organization is a contextual consequence of RB1's core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:1904028 positive regulation of collagen fibril organization
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 affects collagen-fibril organization via transcriptional regulation of stromal programs, but collagen-fibril organization is a contextual consequence of RB1's core role in cell-cycle / differentiation control rather than a primary molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:1904761 negative regulation of myofibroblast differentiation
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Tissue-specific phenotype projected from mouse Rb1 ortholog: Rb1 restricts myofibroblast differentiation programs in fibrotic contexts, but this is a downstream cell-fate consequence of RB1's core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.
Reason: Real biology but a downstream / tissue-specific consequence of RB1's core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.
GO:0005634 nucleus
NAS
PMID:2730637
Homology between a region of the human retinoblastoma gene a... 		ACCEPT
Summary: NAS annotation for nuclear localization derived from Taya et al. 1989 (PMID:2730637), a paper primarily about homology between the RB1 gene and L1 family repetitive sequences. The paper discusses DNA-binding properties of RB1 (which implicitly involves nuclear localization) but does not directly characterize subcellular localization. The NAS evidence is weak as a primary source, but the annotated function (nuclear localization) is independently and robustly supported by IDA evidence (PMID:1531329, PMID:20940255, PMID:17540172), TAS evidence (PMID:3657987 — the original Lee et al. 1987 nuclear-phosphoprotein paper), and 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444).
Reason: The underlying annotation (nuclear localization) is one of the most robustly established RB1 facts, independently supported by multiple IDA/EXP/TAS rows from the foundational literature. The specific NAS source (PMID:2730637) is weak provenance individually, but consistent with the broader literature and not biologically wrong. Mechanical canonical-nuclear-localization batch (batch 10 of #347).
GO:0006355 regulation of DNA-templated transcription
NAS
PMID:2730637
Homology between a region of the human retinoblastoma gene a... 		MODIFY
Summary: NAS annotation derived from Taya et al. 1989 (PMID:2730637), a paper about homology between a region of the RB1 gene and L1-family repetitive sequences that only speculatively "discusses" possible DNA-binding properties of RB1; it does not characterize RB1 transcriptional regulation. The NAS source is therefore weak provenance for this term individually (the same weak-NAS PMID:2730637 situation was handled for the adjacent nuclear-localization row in batch 10). However, the underlying function — RB1 repression of E2F-dependent, DNA-templated transcription — is one of the most robustly established RB1 facts (core_functions[0]) and is directionally negative. The generic GO:0006355 is too broad; the specific child GO:0045892 (negative regulation of DNA-templated transcription) is the curation-preferred term and is independently supported by IDA/TAS evidence elsewhere in this file (PMID:1531329, PMID:12065415, PMID:10783144, PMID:19223331, PMID:19149898).
Reason: Essence (RB1 regulates DNA-templated transcription) is sound and canonical, but the NAS source is a sequence-homology paper and the generic GO:0006355 is too broad for RB1's well-established negative/repressor activity. Replace with the specific GO:0045892 (negative regulation of DNA-templated transcription) already present in core_functions[0]; conservative MODIFY rather than REMOVE, consistent with the batch-10 handling of the weak-NAS PMID:2730637 localization row. Mechanical transcription-regulation batch (batch 20 of #347).
GO:0061676 importin-alpha family protein binding
IPI
PMID:12695505
Structural basis for the specificity of bipartite nuclear lo... 		KEEP AS NON CORE
Summary: IPI annotation for importin-alpha family protein binding sourced from Fontes et al. 2003 (PMID:12695505). This study co-crystallized mammalian importin-alpha with a peptide corresponding to the bipartite nuclear localization sequence of human retinoblastoma protein, defining the structural basis by which importin-alpha specifically recognizes the RB1 NLS. This is genuine, specific (informative) evidence that RB1 binds the importin-alpha nuclear-import receptor.
Reason: RB1-importin-alpha binding is correctly and specifically supported by the PMID:12695505 co-crystal structure and is informative rather than generic protein binding, but it represents the nuclear-import transport mechanism that delivers RB1 to its compartment rather than the defining nuclear E2F-corepressor / chromatin-scaffold activity in core_functions[0]. Kept on record at non-core priority, consistent with the file's treatment of localization/transport mechanisms (e.g., GO:0005737 cytoplasm KEEP_AS_NON_CORE) relative to the core corepressor function. Mechanical binding-partner-MF batch (batch 22 of #347).
GO:0005654 nucleoplasm
IDA
PMID:8245034
Structural and functional characterization of the HPV16 E7 p... 		ACCEPT
Summary: IDA annotation for nucleoplasmic localization sourced from Pahel et al. 1993 (PMID:8245034), an HPV16 E7 biochemistry paper. E7 is a "nuclear phosphoprotein" that binds RB1 "avidly and specifically" and can dissociate the E2F transcription factor from RB1 in vitro. The biochemistry of the E7–RB1 interaction is performed on nuclear RB1, supporting RB1 nucleoplasmic localization. Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 already ACCEPTed (PR #444), by IDA evidence (PMID:17540172 in PR #499, GO_REF:0000052 HPA in this batch), and by canonical IEA propagations ACCEPTed in PR #461.
Reason: Canonical RB1 nucleoplasmic localization, well supported by experimental evidence already present in this file (17 Reactome TAS rows ACCEPTed in PR #444; IDA from PMID:17540172 ACCEPTed in PR #499). The E7-RB1 interaction characterized in PMID:8245034 is well established to occur in the nucleus where RB1 binds chromatin. Mechanical canonical-nuclear-localization batch (batch 10 of #347).
GO:0035189 Rb-E2F complex
IDA
PMID:8245034
Structural and functional characterization of the HPV16 E7 p... 		ACCEPT
Summary: Pahel et al. 1993 (PMID:8245034) characterizes purified HPV16 E7 and shows it "binds the retinoblastoma protein avidly and specifically, and it can dissociate the E2F transcription factor when assayed in vitro." Demonstrating that E7 dissociates E2F from RB1 directly evidences the pre-existing RB1-E2F complex. The Rb-E2F complex is the namesake, canonical RB1 mechanism: the RB_A/RB_B pocket engages activator E2F1/2/3 to occupy E2F target promoters (PMID:7923370; deep research synthesis). This exact GO:0035189 term is already independently ACCEPTed on IBA (GO_REF:0000033, batch 6), IPI (PMID:16360038, batch 17), and IEA (PR #461) evidence elsewhere in this file.
Reason: Canonical core RB1 function — the Rb-E2F complex is the defining RB1 mechanism, independently and robustly supported across IBA/IPI/IEA evidence already ACCEPTed on this exact term in this file. Same canonical-Rb-E2F ACCEPT precedent as the batch-17 PMID:16360038 structural rows. Mechanical canonical-Rb-E2F batch (batch 19 of #347).
GO:0097718 disordered domain specific binding
IPI
PMID:8245034
Structural and functional characterization of the HPV16 E7 p... 		MARK AS OVER ANNOTATED
Summary: Pahel et al. 1993 (PMID:8245034) is an HPV16 E7 biochemistry paper showing E7 (an intrinsically disordered viral oncoprotein) binds RB1 and dissociates E2F. GO:0097718 disordered domain specific binding is a generic, uninformative binding term that does not capture RB1's specific LxCxE-cleft / RB_A-RB_B pocket adapter biology, and the paper does not set out to characterize RB1's binding specificity for disordered domains as such. The informative interaction from this paper is already captured by the ACCEPTed GO:0035189 (Rb-E2F complex) row from the same reference.
Reason: Generic, uninformative binding term for RB1's well-characterized adapter/scaffolding biology, derived from an HPV E7 biochemistry paper rather than a study of RB1 disordered-domain binding specificity. Conservative demotion consistent with the uniform GO:0005515 protein-binding precedent in this same review and the batch-18 PMID:16360038 generic-binding handling (GO:0042802 / GO:0051219). Mechanical generic-binding batch (batch 19 of #347).
GO:0010629 negative regulation of gene expression
IMP
PMID:25100735
Post-transcriptional gene expression control by NANOS is up-... 		ACCEPT
Summary: IMP annotation from Miles et al. 2014 (PMID:25100735), which shows that NANOS (NANOS1/NANOS3) "is directly repressed by pRb/E2F in flies and humans." siRNA depletion of the pocket proteins (including pRb) from human BJ fibroblasts produced "a strong up-regulation in the expression of the NANOS1 and NANOS3 genes," and ChIP showed that dREAM (E2F4/p107/p130) occupancy at the NANOS1 promoter is pRb-dependent. This is direct functional (IMP) evidence that RB1 negatively regulates target-gene expression — a canonical instance of RB1's defining transcriptional corepressor activity (core_functions[0]), concordant with the GO:0045892 IDA/TAS rows ACCEPTed elsewhere in this file (PMID:12065415, PMID:10783144, PMID:19223331, PMID:19149898).
Reason: Canonical RB1 transcriptional repressor activity — pRb directly represses NANOS1/3 expression (IMP via pocket-protein depletion plus dREAM-promoter ChIP). Maps to core_functions[0] (Rb-E2F transcriptional corepressor) and is independently supported by the GO:0045892 negative-regulation rows already ACCEPTed in this file. Mechanical transcription-regulation batch (batch 20 of #347).
GO:2000679 positive regulation of transcription regulatory region DNA binding
IDA
PMID:25100735
Post-transcriptional gene expression control by NANOS is up-... 		KEEP AS NON CORE
Summary: IDA annotation from Miles et al. 2014 (PMID:25100735). ChIP experiments show that pRb stabilizes binding of the dREAM repressor components (E2F4, p107, p130) at the NANOS1 promoter: "these observations suggest that pRb stabilizes dREAM-binding to the NANOS1 promoter," and "the binding of these dREAM components to the NANOS1 promoter was dramatically reduced by knockdown of pRb." This biologically supports GO:2000679 (RB1 positively regulating occupancy of a transcription regulatory region by the repressor complex); the finding is correct and not an over-annotation. However, it describes a fine-grained downstream mechanistic consequence of RB1's repressor scaffold rather than RB1's core function; the core activity (transcriptional corepression / negative regulation of DNA-templated transcription) is already captured in core_functions[0].
Reason: Biologically correct and IDA-supported (pRb stabilizes dREAM/E2F4 occupancy at the NANOS1 promoter), but a specific mechanistic detail of the repressor-scaffold mechanism rather than a core RB1 function. Retain as non-core; the core repressor activity is represented by core_functions[0] and the GO:0045892 rows. Mechanical transcription-regulation batch (batch 20 of #347).
GO:0005515 protein binding
IPI
PMID:12037672
Physical interaction between pRb and cdk9/cyclinT2 complex. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0008024 cyclin/CDK positive transcription elongation factor complex
IDA
PMID:12037672
Physical interaction between pRb and cdk9/cyclinT2 complex. 		MARK AS OVER ANNOTATED
Summary: IDA cellular-component annotation citing Simone et al. 2002 (PMID:12037672), "Physical interaction between pRb and cdk9/cyclinT2 complex." That paper demonstrates an in vitro and in vivo physical interaction between pRb (C-terminal domain, residues 835-928) and the cdk9/cyclinT2 complex, and maps cdk9-mediated phosphorylation of the pRb C-terminus (S795/S807/S811). pRb is thus an interactor and phosphorylation substrate of cdk9/cyclinT2 (P-TEFb), not a constitutive structural subunit of the cyclin/CDK positive transcription elongation factor complex (GO:0008024). The authors themselves describe pRb and cdk9/cyclinT2 as "located in a nuclear multiprotein complex," i.e. a transient/regulatory association, which does not establish stable membership of the P-TEFb elongation factor complex itself.
Reason: The cited evidence supports a physical interaction with and phosphorylation by cdk9/cyclinT2, but a CC complex-membership term (GO:0008024) implies pRb is a stable subunit of P-TEFb, which the source does not establish — pRb is a substrate/interactor, not a core subunit. Conservative demotion (the association is real, so not REMOVE) consistent with the in-file handling of interaction-derived over-specific terms (e.g. the GO:0042802/PMID:16360038 batch-17 demotion). The genuine pRb-cdk9 interaction is better represented as a binding/phospho-substrate relationship than as P-TEFb complex membership.
GO:0005515 protein binding
IPI
PMID:15107404
Liver tumors escape negative control of proliferation via PI... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-188191 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-2172666 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9018017 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9659820 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9686969 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9686980 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9768288 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-NUL-8985474 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005654 nucleoplasm
TAS
Reactome:R-NUL-8985490 		ACCEPT
Summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
Reason: Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).
GO:0005515 protein binding
IPI
PMID:7651420
Characterization of a novel 350-kilodalton nuclear phosphopr... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0045892 negative regulation of DNA-templated transcription
IDA
PMID:12065415
Prohibitin requires Brg-1 and Brm for the repression of E2F ... 		ACCEPT
Summary: IDA annotation supporting RB1's canonical role as a negative regulator of DNA-templated transcription, sourced from the Prohibitin/Brg-1/Brm paper (PMID:12065415) which directly shows that pRb-mediated repression of E2F-target gene promoters and the resulting cell-growth suppression require the SWI/SNF chromatin remodelers BRG1/SMARCA4 and BRM. Negative regulation of DNA-templated transcription is RB1's defining transcriptional activity at E2F-target promoters (PMID:7923370; deep research synthesis), already captured in core_functions[0] (Rb-E2F transcriptional corepressor) and independently supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347).
Reason: Canonical RB1 corepressor activity, well anchored to the pRb-E2F repressor model and to RB1's SWI/SNF (BRG1/BRM) chromatin-remodeler partnership already supported elsewhere in this file (GO:0006338 chromatin remodeling TAS PMID:19149898 ACCEPTed, GO:0016514 SWI/SNF complex TAS ACCEPTed). The PMID:12065415 paper provides direct experimental evidence (IDA) for pRb-mediated repression at E2F-target promoters via prohibitin/SWI/SNF cooperation. Mechanical canonical-corepressor IDA batch (batch 13 of #347) — 3 IDA rows on GO:0045892 from primary literature uniformly consolidated to ACCEPT.
GO:0007346 regulation of mitotic cell cycle
IMP
PMID:20551165
Loss of pRB causes centromere dysfunction and chromosomal in... 		KEEP AS NON CORE
Summary: IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB depletion slows mitotic progression and promotes aneuploidy through compromised centromere function and chromosome cohesion (CAP-D3/condensin II mislocalization, merotelic attachment, lagging chromosomes). Real RB1 biology — RB1 loss alters mitotic timing/fidelity — but this is a non-cell-cycle-arrest mitotic phenotype downstream of RB1's primary G1/S corepressor activity, and "regulation of mitotic cell cycle" is a very broad parent term that does not capture the specific Manning et al. mitotic-fidelity mechanism.
Reason: RB1's contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1's primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.
GO:0031134 sister chromatid biorientation
IMP
PMID:20551165
Loss of pRB causes centromere dysfunction and chromosomal in... 		KEEP AS NON CORE
Summary: IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB depletion causes merotelic kinetochore-microtubule attachments and failure of chromosome congression — the cellular consequence of compromised centromere/cohesion architecture (CAP-D3/condensin II mislocalization, increased intercentromeric distance). Sister chromatid biorientation defects directly explain the lagging chromosomes and missegregation phenotype reported in the paper. Real RB1 biology but a non-core mitotic-fidelity role rather than RB1's defining transcriptional corepressor activity.
Reason: RB1's contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1's primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.
GO:0034088 maintenance of mitotic sister chromatid cohesion
IMP
PMID:20551165
Loss of pRB causes centromere dysfunction and chromosomal in... 		KEEP AS NON CORE
Summary: IMP annotation from Manning et al. 2010 (PMID:20551165), which directly showed that pRB depletion compromises centromeric chromosome cohesion (increased intercentromeric distance, deformed centromeric structure) via mislocalization of CAP-D3/condensin II. The paper explicitly identifies cohesion maintenance at centromeres as a function disrupted by pRB loss. Real RB1 biology — RB1 is required for maintenance of mitotic centromere cohesion via the condensin II pathway — but this is a non-core mitotic-fidelity role rather than RB1's defining transcriptional corepressor activity.
Reason: RB1's contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1's primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.
GO:0045842 positive regulation of mitotic metaphase/anaphase transition
IMP
PMID:20551165
Loss of pRB causes centromere dysfunction and chromosomal in... 		KEEP AS NON CORE
Summary: IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB-depleted cells experience mitotic delay with lagging chromosomes following compromised centromere cohesion and merotelic attachment. The "positive regulation of metaphase/anaphase transition" framing reflects the paper's observation that loss of pRB impairs timely progression through metaphase/anaphase due to faulty kinetochore-microtubule attachments and the resulting spindle checkpoint engagement. Real RB1 biology — RB1 supports timely metaphase-to-anaphase progression by maintaining the centromere/cohesion architecture required for proper kinetochore attachment — but this is a non-core mitotic-fidelity role rather than RB1's defining transcriptional corepressor activity.
Reason: RB1's contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1's primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.
GO:0071459 protein localization to chromosome, centromeric region
IMP
PMID:20551165
Loss of pRB causes centromere dysfunction and chromosomal in... 		KEEP AS NON CORE
Summary: IMP annotation from Manning et al. 2010 (PMID:20551165), which directly showed that pRB depletion compromises centromeric localization of CAP-D3/condensin II — the most specific molecular finding of the paper and the mechanistic basis for the downstream cohesion/segregation defects. RB1 is required for proper recruitment of the condensin II complex to centromeric chromatin. Real RB1 biology — RB1 supports centromeric protein localization via condensin II recruitment — but this is a non-core mitotic-fidelity role rather than RB1's defining transcriptional corepressor activity.
Reason: RB1's contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1's primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.
GO:0005515 protein binding
IPI
PMID:20870719
Methylation of the retinoblastoma tumor suppressor by SMYD2. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:16964284
Prohibitin, a protein downregulated by androgens, represses ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:11571652
The de-ubiquitinating enzyme Unp interacts with the retinobl... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:10613832
Reduced stability of retinoblastoma protein by gankyrin, an ... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0045892 negative regulation of DNA-templated transcription
IDA
PMID:19223331
HMGB1 and HMGB2 proteins up-regulate cellular expression of ... 		ACCEPT
Summary: IDA annotation supporting RB1's canonical role as a negative regulator of DNA-templated transcription, sourced from the HMGB1/HMGB2 topoisomerase IIalpha paper (PMID:19223331) which characterizes pRb-mediated repression of the human topoisomerase IIalpha promoter and the antagonistic activity of HMGB1/HMGB2 on this repression. The paper provides direct experimental evidence (IDA) for pRb-mediated repression of an endogenous promoter. Negative regulation of DNA-templated transcription is RB1's defining transcriptional activity (PMID:7923370; deep research synthesis), already captured in core_functions[0] (Rb-E2F transcriptional corepressor) and independently supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347).
Reason: Canonical RB1 corepressor activity demonstrated by direct experimental evidence (IDA) on an endogenous target promoter (TOP2A). PMID:19223331 frames pRb as a repressor of the human topoisomerase IIalpha promoter that HMGB1/HMGB2 counteract. Consistent with RB1's defining corepressor activity already captured by core_functions[0] and supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347) and analogous IDA/IMP rows elsewhere in this file. Mechanical canonical-corepressor IDA batch (batch 13 of #347) — 3 IDA rows on GO:0045892 from primary literature uniformly consolidated to ACCEPT.
GO:0005515 protein binding
IPI
PMID:7503932
Dual retinoblastoma-binding proteins with properties related... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0007265 Ras protein signal transduction
IEP
PMID:9054499
Oncogenic ras provokes premature cell senescence associated ... 		REMOVE
Summary: IEP annotation citing Serrano et al. 1997 (PMID:9054499), "Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a." That paper establishes that oncogenic RAS induces a permanent G1 arrest (oncogene-induced senescence) accompanied by accumulation of p53 and p16INK4a, with p16/p53 inactivation preventing the arrest. RB1 is not characterized in this study as a Ras-pathway transducer; its only relationship to this work is as a downstream effector of the p16INK4a-CDK4/6 arm engaged during RAS-induced senescence. GO:0007265 Ras protein signal transduction denotes the small-GTPase Ras signaling relay itself (GEF/GAP/effector cascade), of which RB1 is categorically not a member.
Reason: Categorical functional-class mismatch: RB1 is a chromatin-bound transcriptional corepressor / G1-S effector, not a component or regulator of the Ras GTPase signal-transduction cascade (GO:0007265). The IEP source (PMID:9054499) is a p16/p53 oncogene-induced-senescence paper that does not interrogate RB1's role in Ras signaling at all. Per the schema, a wrong functional class (REMOVE, "unlikely to be correct based on combined evidence") is distinct from over-granularity (MARK_AS_OVER_ANNOTATED); this is the former, following the in-file batch-22 GO:0031625/PMID:10944455 REMOVE precedent for an evidence-class mismatch. RB1's genuine downstream role in RAS/oncogene-induced senescence would belong as a senescence/cell-cycle annotation with its own source, not as Ras signal transduction.
GO:0005515 protein binding
IPI
PMID:15542589
LIM domains-containing protein 1 (LIMD1), a tumor suppressor... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:10783144
Identification of a novel partner of RNA polymerase II subun... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0045892 negative regulation of DNA-templated transcription
IDA
PMID:10783144
Identification of a novel partner of RNA polymerase II subun... 		ACCEPT
Summary: IDA annotation supporting RB1's canonical role as a negative regulator of DNA-templated transcription, sourced from the Che-1/AATF paper (PMID:10783144) — "Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which interacts with and affects the growth suppression function of Rb." The paper demonstrates pRb's growth-suppression activity at Pol II-driven gene programs and shows that Che-1 (AATF, the human Bfr2 homolog) modulates this activity through its interaction with Rb. Negative regulation of DNA-templated transcription is RB1's defining transcriptional activity (PMID:7923370; deep research synthesis), already captured in core_functions[0] (Rb-E2F transcriptional corepressor) and independently supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347).
Reason: Canonical RB1 corepressor activity demonstrated by direct experimental evidence (IDA) on Pol II-driven growth-suppression promoter activity, in the context of the Che-1/AATF interaction with Rb. Consistent with RB1's defining corepressor activity already captured by core_functions[0] and supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347) and analogous IDA rows on this term elsewhere in this file. Mechanical canonical-corepressor IDA batch (batch 13 of #347) — 3 IDA rows on GO:0045892 from primary literature uniformly consolidated to ACCEPT.
GO:0051219 phosphoprotein binding
IPI
PMID:16360038
Structure of the Rb C-terminal domain bound to E2F1-DP1: a m... 		MARK AS OVER ANNOTATED
Summary: Rubin et al. 2005 (PMID:16360038, Cell) demonstrates that CDK phosphorylation of RB1 itself drives E2F release: phosphorylation at S788/S795 directly destabilizes one set of RbC-E2F-DP contacts, while phosphorylation at T821/T826 induces an intramolecular RbC-pocket interaction that destabilizes the remaining contacts. RB1 is the phosphoprotein in this mechanism and phosphorylation promotes dissociation; the paper does not show RB1 binding to a phosphorylated partner protein. GO:0051219 phosphoprotein binding (binding a phosphorylated protein) is therefore not supported by this evidence and mischaracterizes the phospho-regulation-of-RB1 / E2F-release mechanism the paper actually establishes.
Reason: The cited paper characterizes phosphorylation OF RB1 driving E2F release, the opposite of RB1 binding a phosphoprotein partner; the term is unsupported by this source. Conservative demotion consistent with the GO:0005515 precedent in this review and the batch-17 handling of PMID:16360038.
GO:0045445 myoblast differentiation
IMP
PMID:15541338
Regulation of Rb gene expression by an MBD2-interacting zinc... 		KEEP AS NON CORE
Summary: IMP annotation citing Sekimata & Homma 2004 (PMID:15541338), "Regulation of Rb gene expression by an MBD2-interacting zinc finger protein MIZF during myogenic differentiation." The study shows MIZF represses Rb transcription; forced MIZF expression in C2C12 myoblasts lowers Rb (and myogenin/Troponin-T) and blocks differentiation into multinucleated myotubes, indicating that induction of Rb expression is required for myogenic differentiation. RB1's pro-differentiation role in the myogenic lineage is well established (deep research synthesis; corroborated by PMID:9448006 discussion noting nonphosphorylated pRB promotes myocyte differentiation). The evidence here is somewhat indirect (it manipulates MIZF rather than RB1 directly), but the conclusion that Rb is needed for myoblast differentiation is consistent with the broader literature.
Reason: RB1's role in myoblast/myogenic differentiation is real and literature-supported but is a lineage-specific developmental context downstream of the defining Rb-E2F cell-cycle-exit/transcriptional-corepressor activity (core_functions[0]; ACCEPTed GO:0051726, GO:0045892 rows), not a core molecular function. Retained on record as non-core, consistent with the GO:0032502 developmental process KEEP_AS_NON_CORE decision in this batch and the broader non-core differentiation/senescence framing in the deep research synthesis.
GO:0005515 protein binding
IPI
PMID:17540172
L3MBTL1, a histone-methylation-dependent chromatin lock. 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0031625 ubiquitin protein ligase binding
IPI
PMID:10944455
RBP95, a novel leucine zipper protein, binds to the retinobl... 		REMOVE
Summary: IPI annotation for ubiquitin protein ligase binding citing Wen & Ao 2000 (PMID:10944455). That paper characterizes RBP95, a novel 838-residue basic-region leucine-zipper protein that binds pRb through a conserved LXCXE motif engaging the entire pocket region, and proposes RBP95 functions in RNA polymerase II-mediated transcription/processing. RBP95 is not a ubiquitin protein ligase and the study describes no ubiquitin-ligase activity, ubiquitination, or E3-ligase interaction; the cited evidence therefore does not support the term GO:0031625 ubiquitin protein ligase binding.
Reason: The cited source does not support GO:0031625: PMID:10944455 (Wen & Ao 2000) characterizes RBP95, an LXCXE-motif basic-region leucine-zipper transcription-associated partner with no ubiquitin-ligase activity, RING/HECT domain, or ubiquitination assay. The evidence gap is categorical (a bZIP transcription partner vs. a ubiquitin protein ligase are unrelated functional classes), not a matter of over-granularity, so per the schema this is REMOVE ("unlikely to be correct based on combined evidence") rather than MARK_AS_OVER_ANNOTATED ("not entirely wrong... over-annotation"). This differs from the in-file GO:0042802/PMID:16360038 precedent, where the evidence was within the correct functional class but heterotypic rather than homotypic (a scope issue). If separate evidence exists that RB1 binds a ubiquitin ligase, it belongs as a new annotation with its own source. Mechanical binding-partner-MF batch (batch 22 of #347).
GO:0006338 chromatin remodeling
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes pRb-mediated chromatin remodeling at E2F-target promoters via recruitment of BRM, BRG1/SMARCA4 (SWI/SNF catalytic subunit), and HDAC1. Chromatin remodeling is a canonical RB1 BP activity supported by extensive primary literature (PMID:7923370; deep research synthesis).
Reason: Chromatin remodeling via SWI/SNF and histone-deacetylase recruitment is a canonical mechanism for RB1-mediated E2F repression. PMID:19149898 directly states pRb "can repress gene transcription at least partly by remodelling chromatin structure through its interactions with proteins such as HDAC1, BRM and BRG1." Mechanical TAS batch (batch 9 of #347).
GO:0016514 SWI/SNF complex
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes RB1 association with the SWI/SNF chromatin-remodeling complex via the catalytic subunits BRM and BRG1/SMARCA4. The RB1-BRG1 interaction recruits SWI/SNF to E2F-responsive promoters to enhance pRb transcriptional repressor activity (cited refs 4 and 5 in Becker et al.).
Reason: RB1's recruitment of SWI/SNF to E2F-target chromatin is one of the canonical chromatin-coregulator interactions for RB1, with direct biochemical support across multiple primary papers. PMID:19149898 explicitly describes "BRG1, as the catalytic core of the SWI/SNF chromatin remodelling complex, the interaction between BRG1 and pRb was proposed to recruit the complex to E2F responsive promoters." Mechanical TAS batch (batch 9 of #347).
GO:0035189 Rb-E2F complex
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes "active pRb-E2F transcriptional repressor complexes that silence genes required for S-phase entry." Rb-E2F complex membership is the defining biochemical complex for RB1's tumor-suppressor function and is already independently captured in this file by IBA (PR #490) and IPI (PMID:8245034) evidence.
Reason: Rb-E2F complex membership is the defining biochemical complex for RB1's tumor-suppressor activity at the G1/S restriction point. PMID:19149898 directly anchors this annotation to the active pRb-E2F repressor complex framework. Mechanical TAS batch (batch 9 of #347).
GO:0045892 negative regulation of DNA-templated transcription
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews pRb as a transcriptional corepressor that silences E2F-target genes via chromatin remodeling. Negative regulation of DNA-templated transcription is the general BP parent of the canonical pRb-E2F repression activity (GO:0000122 is the Pol II-specific child) and is already supported by IDA evidence on PMID:12065415 and PMID:10783144 elsewhere in this file.
Reason: Negative regulation of DNA-templated transcription is a canonical RB1 activity, well anchored to the pRb-E2F repressor model that PMID:19149898 reviews. Mechanical TAS batch (batch 9 of #347).
GO:0051726 regulation of cell cycle
TAS
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding par... 		ACCEPT
Summary: TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews the canonical p16INK4a–Cyclin D-CDK4/6–pRb–E2F G1/S switch. Regulation of cell cycle is a canonical RB1 BP, already captured in this file via IEA propagation (GO_REF:0000120) and by multiple direct experimental rows on G1/S regulators.
Reason: Regulation of the cell cycle is one of the defining RB1 tumor-suppressor functions, central to the existing core_functions[0] block (G1/S restriction). PMID:19149898 directly anchors RB1 to the canonical CDK4/6-cyclin D-pRb-E2F G1/S switch. Mechanical TAS batch (batch 9 of #347).
GO:0005515 protein binding
IPI
PMID:11073990
A novel Rb- and p300-binding protein inhibits transactivatio... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0005515 protein binding
IPI
PMID:9448006
The promyelocytic leukemia gene product (PML) forms stable c... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0016605 PML body
IDA
PMID:9448006
The promyelocytic leukemia gene product (PML) forms stable c... 		KEEP AS NON CORE
Summary: IDA annotation citing Alcalay et al. 1998 (PMID:9448006), "The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein." By immunofluorescence the authors directly demonstrate that endogenous nonphosphorylated (hypophosphorylated) pRB colocalizes with PML within PML nuclear bodies (NBs), and that PML and pRB form stable complexes in vivo via the pRB pocket region; PML-RARalpha expression delocalizes pRB from the NBs. This is direct experimental evidence (IDA) for localization of a fraction of hypophosphorylated pRB to PML bodies. PML-NB localization is a specific subnuclear context linked to growth suppression / differentiation / senescence, distinct from the canonical nucleoplasmic E2F-target-promoter localization that constitutes RB1's core compartment.
Reason: Directly demonstrated (IDA) localization of hypophosphorylated pRB to PML nuclear bodies is real but represents a specialized, low-stoichiometry (~0.5-1%) subnuclear pool in a growth-suppressive/differentiation context, not the canonical nucleoplasmic compartment where active RB1 occupies E2F-target promoters (captured by the ACCEPTed GO:0005654 nucleoplasm Reactome TAS rows). Retained as a real non-core localization, same precedent as the GO:0005819 spindle (batch 15, #551) and GO:0005737 cytoplasm KEEP_AS_NON_CORE rows.
GO:0005515 protein binding
IPI
PMID:9395244
Phosphorylated retinoblastoma protein stimulates DNA polymer... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0019900 kinase binding
IDA
PMID:16286473
The retinoblastoma family proteins bind to and activate diac... 		KEEP AS NON CORE
Summary: IDA annotation for kinase binding sourced from Los et al. 2006 (PMID:16286473, J Biol Chem). The paper demonstrates that hypophosphorylated pRB binds directly to the lipid kinase diacylglycerol kinase zeta (DGKzeta) in vitro and in vivo (pRB had previously been shown to bind phosphatidylinositol-4-phosphate 5-kinases), with binding dependent on pRB phosphorylation status [PMID:16286473 "DGKzeta ... interacts with pRB in vitro and in vivo. Binding of DGKzeta to pRB is dependent on the phosphorylation status of pRB, since only hypophosphorylated pRB interacts with DGKzeta"]. GO:0019900 is appropriately informative and preferred over the generic GO:0005515 protein binding rows uniformly demoted elsewhere in this file, and the direct binding is well supported. This lipid-kinase effector interaction is a peripheral, non-core relationship — RB1's core molecular function is E2F-DP pocket binding and chromatin-corepressor recruitment (core_functions[0]), not lipid-signaling enzyme binding.
Reason: Direct, phosphorylation-dependent pRB–DGKzeta binding is well supported by IDA evidence in PMID:16286473, and GO:0019900 (kinase binding) is appropriately informative (preferred over generic protein binding per CLAUDE.md). Retained as non-core because the DGKzeta/lipid-kinase interaction is a downstream effector relationship peripheral to RB1's canonical E2F-pocket/chromatin tumor-suppressor function. Kinase-interaction cluster (batch 21 of #347).
GO:0043550 regulation of lipid kinase activity
IDA
PMID:16286473
The retinoblastoma family proteins bind to and activate diac... 		MODIFY
Summary: IDA annotation for regulation of lipid kinase activity sourced from Los et al. 2006 (PMID:16286473, J Biol Chem). The paper shows that pRB (and the related pocket proteins p107 and p130) specifically and potently STIMULATE the activity of the lipid kinase DGKzeta in vitro [PMID:16286473 "we found that pRB, p107, and p130 potently stimulate DGKzeta activity in vitro"], proposing DGKzeta as a downstream effector of pRB that regulates nuclear diacylglycerol/phosphatidic acid levels. The recorded term GO:0043550 (regulation of lipid kinase activity) is directionally unspecified and therefore too general for this evidence, which demonstrates positive regulation/stimulation specifically. This is a peripheral, non-core lipid-signaling effector role rather than RB1's canonical E2F/cell-cycle function.
Reason: Essence (RB1 regulates a lipid kinase) is sound and supported by IDA in PMID:16286473, but the data specifically show stimulation/activation of DGKzeta, so the directionally-neutral GO:0043550 is too general. Replace with the specific child GO:0090218 (positive regulation of lipid kinase activity); conservative MODIFY rather than ACCEPT-as-is, consistent with the batch-20 handling of the over-general GO:0006355 transcription row. Non-core lipid-signaling effector role. Kinase-interaction cluster (batch 21 of #347).
GO:0005515 protein binding
IPI
PMID:9858607
Rb inhibits the intrinsic kinase activity of TATA-binding pr... 		MARK AS OVER ANNOTATED
Summary: This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.
Reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
GO:0006469 negative regulation of protein kinase activity
IPI
PMID:9858607
Rb inhibits the intrinsic kinase activity of TATA-binding pr... 		KEEP AS NON CORE
Summary: IPI annotation for negative regulation of protein kinase activity sourced from Siegert & Robbins 1999 (PMID:9858607, Mol Cell Biol). The large pocket of Rb binds directly to the TFIID subunit TAFII250 (TAF1) and dose-responsively inhibits its intrinsic, bipartite kinase activity — both TAFII250 autophosphorylation and transphosphorylation of the RAP74 subunit of TFIIF [PMID:9858607 "Rb is able to inhibit the kinase activity of immunopurified and gel-purified recombinant TAFII250. Rb inhibits the autophosphorylation of TAFII250 as well as its phosphorylation of the RAP74 subunit of TFIIF in a dose-responsive manner"]. Tumor-derived Rb pocket mutants are functionally defective for this kinase inhibition despite retaining binding [PMID:9858607 "two different tumor-derived Rb pocket mutants, C706F and Deltaex22, are functionally defective for kinase inhibition, even though they are able to bind the amino terminus of TAFII250"], linking the activity to the tumor-suppressor pocket. GO:0006469 is well supported and specific. The authors frame this as a novel, promoter-context-specific transcriptional-regulation mechanism — a peripheral facet rather than RB1's canonical E2F-masking/chromatin-corepressor core function.
Reason: Direct, dose-responsive Rb inhibition of TAFII250 (TAF1) kinase activity is well supported in PMID:9858607, and GO:0006469 (negative regulation of protein kinase activity) is specific and accurate. Retained as non-core because the authors frame it as a novel, promoter-specific accessory mechanism of transcriptional repression, distinct from RB1's canonical E2F-pocket/chromatin-corepressor core function (core_functions[0]). Kinase-interaction cluster (batch 21 of #347).

Core Functions

RB1 functions as the canonical transcriptional corepressor of the pocket protein family. Through its RB_A/RB_B pocket domains it binds activator E2F transcription factors (E2F1/2/3) on the promoters of S-phase genes, masks their transactivation domains and recruits chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, polycomb and DNA methyltransferase activities) to durably silence the E2F transcriptional program in G0/G1 cells. This activity defines the G1 restriction point and is the most highly conserved evolved function of pocket proteins. RB1 is held in this active corepressor state when hypo- or mono-phosphorylated, and is sequentially inactivated by Cyclin-CDK complexes (Cyclin D-CDK4/6, Cyclin E-CDK2) that hyperphosphorylate ~16 Ser/Thr sites (e.g. T373, S608, S780, S807/S811, T826), releasing E2F to drive S-phase entry.

Molecular Function:
transcription corepressor activity
Directly Involved In:
negative regulation of G1/S transition of mitotic cell cycle negative regulation of DNA-templated transcription
Cellular Locations:
nucleus chromatin
In Complex:
Rb-E2F complex
Supporting Evidence:
  • PMID:7923370
    The retinoblastoma tumor suppressor protein (RB) binds several cellular proteins involved in cell cycle progression.
  • PMID:7923370
    BRG1 contains an RB-binding motif found in viral oncoproteins and bound to the A/B pocket and the hypophosphorylated form of RB.
  • file:human/RB1/RB1-deep-research-falcon.md
    pRb's primary function is to enforce the G1 restriction point by binding and repressing activator E2Fs (classically E2F1/2/3) and thereby suppressing transcriptional programs required for DNA replication and S-phase entry
  • file:human/RB1/RB1-deep-research-falcon.md
    RB can repress E2F-dependent transcription both by masking E2F transactivation domains and by recruiting chromatin modifiers
  • file:human/RB1/RB1-deep-research-falcon.md
    RB-mediated repression is supported by recruitment of chromatin modifiers, including HDACs, DNA methyltransferases, and SUV39H1
  • file:human/RB1/RB1-deep-research-falcon.md
    RB activity is classically regulated by cyclin-CDK phosphorylation, which weakens RB's repression of E2F and allows cell-cycle progression

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10613832
Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas.
PMID:10779361
Mutagenesis of the pRB pocket reveals that cell cycle arrest functions are separable from binding to viral oncoproteins.
PMID:10783144
Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which interacts with and affects the growth suppression function of Rb.
PMID:10944455
RBP95, a novel leucine zipper protein, binds to the retinoblastoma protein.
PMID:11073990
A novel Rb- and p300-binding protein inhibits transactivation by MyoD.
PMID:11268000
Ebp1, an ErbB-3 binding protein, interacts with Rb and affects Rb transcriptional regulation.
PMID:11571652
The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein.
PMID:12037672
Physical interaction between pRb and cdk9/cyclinT2 complex.
PMID:12065415
Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth.
PMID:12434308
Protein Phosphatase 1 binds strongly to the retinoblastoma protein but not to p107 or p130 in vitro and in vivo.
PMID:12502741
Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor.
PMID:12598654
Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation.
PMID:12695505
Structural basis for the specificity of bipartite nuclear localization sequence binding by importin-alpha.
PMID:12743606
The adenovirus E1A oncoprotein recruits the cellular TRRAP/GCN5 histone acetyltransferase complex.
PMID:12813456
Interaction of the HPV E7 proteins with the pCAF acetyltransferase.
PMID:1331501
Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins.
PMID:14555653
LEK1 is a potential inhibitor of pocket protein-mediated cellular processes.
PMID:14645241
Interactions between activating signal cointegrator-2 and the tumor suppressor retinoblastoma in androgen receptor transactivation.
PMID:15084261
Cyclin C/cdk3 promotes Rb-dependent G0 exit.
PMID:15107404
Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity.
PMID:1531329
The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F.
PMID:15541338
Regulation of Rb gene expression by an MBD2-interacting zinc finger protein MIZF during myogenic differentiation.
PMID:15542589
LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at chromosome 3p21.3, binds pRB and represses E2F-driven transcription.
PMID:16061792
Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600.
PMID:16249186
Structure of the human Papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor.
PMID:16286473
The retinoblastoma family proteins bind to and activate diacylglycerol kinase zeta.
PMID:16360038
Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release.
PMID:16374512
DNA-damage-responsive acetylation of pRb regulates binding to E2F-1.
PMID:16510145
Effects of MdmX on Mdm2-mediated downregulation of pRB.
PMID:16616919
The arginine methyltransferase PRMT2 binds RB and regulates E2F function.
PMID:16763564
Roles for APIS and the 20S proteasome in adenovirus E1A-dependent transcription.
PMID:16766265
HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity.
PMID:16964284
Prohibitin, a protein downregulated by androgens, represses androgen receptor activity.
PMID:17045206
p53 family members in myogenic differentiation and rhabdomyosarcoma development.
PMID:17274640
A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis.
PMID:17292836
Structure of the oncoprotein gankyrin in complex with S6 ATPase of the 26S proteasome.
PMID:17349581
Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas.
PMID:17380128
Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage.
PMID:17540172
L3MBTL1, a histone-methylation-dependent chromatin lock.
PMID:17620057
Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1.
PMID:18391203
EBV-encoded EBNA-6 binds and targets MRS18-2 to the nucleus, resulting in the disruption of pRb-E2F1 complexes.
PMID:1870208
Purification and characterization of human papillomavirus type 16 E7 protein with preferential binding capacity to the underphosphorylated form of retinoblastoma gene product.
PMID:19017275
Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein.
PMID:19149898
The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a.
PMID:19223331
HMGB1 and HMGB2 proteins up-regulate cellular expression of human topoisomerase IIalpha.
PMID:19249677
Proapoptotic function of the retinoblastoma tumor suppressor protein.
PMID:19417128
Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice.
PMID:19513100
Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis.
PMID:19651603
Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein.
PMID:20088881
Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein. Structural modularity, intrinsic disorder and phosphorylation of human papillomavirus E7.
PMID:20195357
A comprehensive resource of interacting protein regions for refining human transcription factor networks.
PMID:20551165
Loss of pRB causes centromere dysfunction and chromosomal instability.
PMID:20870719
Methylation of the retinoblastoma tumor suppressor by SMYD2.
PMID:20871633
p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb-Hdm2 interaction and apoptosis.
PMID:20940255
Acetylation of Rb by PCAF is required for nuclear localization and keratinocyte differentiation.
PMID:21119616
Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein.
PMID:21139044
Rb-Raf-1 interaction disruptor RRD-251 induces apoptosis in metastatic melanoma cells and synergizes with dacarbazine.
PMID:2138977
The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV40 large T antigen are common sites for mutations.
PMID:2153075
The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation.
PMID:2162480
Definition of the minimal simian virus 40 large T antigen- and adenovirus E1A-binding domain in the retinoblastoma gene product.
PMID:2189724
Two distinct and frequently mutated regions of retinoblastoma protein are required for binding to SV40 T antigen.
PMID:21903422
Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.
PMID:21952639
NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor.
PMID:22157815
The SNF2-like helicase HELLS mediates E2F3-dependent transcription and cellular transformation.
PMID:22301153
The coronavirus endoribonuclease Nsp15 interacts with retinoblastoma tumor suppressor protein.
PMID:22366686
Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells.
PMID:22615382
H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.
PMID:22773103
LEDGF (p75) promotes DNA-end resection and homologous recombination.
PMID:22810586
Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins.
PMID:22898364
Comparative analysis of virus-host interactomes with a mammalian high-throughput protein complementation assay based on Gaussia princeps luciferase.
PMID:23472054
The ING1a tumor suppressor regulates endocytosis to induce cellular senescence via the Rb-E2F pathway.
PMID:23602568
The protein interaction landscape of the human CMGC kinase group.
PMID:23752268
The functional interactome landscape of the human histone deacetylase family.
PMID:23783631
Modulation of allostery by protein intrinsic disorder.
PMID:23859194
Mitogen-activated protein kinase p38 and retinoblastoma protein signalling is required for DNA damage-mediated formation of senescence-associated heterochromatic foci in tumour cells.
PMID:24027266
MiR-26b, upregulated in Alzheimer's disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons.
PMID:24823443
HAUSP, a novel deubiquitinase for Rb - MDM2 the critical regulator.
PMID:25100735
Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells.
PMID:25609649
Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
PMID:25814554
Phospho-tyrosine dependent protein-protein interaction network.
PMID:2730637
Homology between a region of the human retinoblastoma gene and L1 family repetitive sequences.
PMID:29521627
A compartmentalized signaling network mediates crossover control in meiosis.
PMID:29997244
LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.
PMID:32707033
Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
PMID:34591612
A protein interaction landscape of breast cancer.
PMID:34591642
A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
PMID:35140242
Human transcription factor protein interaction networks.
PMID:3657987
The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity.
PMID:39938803
Structural and functional analysis of cancer-associated missense variants in the retinoblastoma protein pocket domain.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
PMID:7503932
Dual retinoblastoma-binding proteins with properties related to a negative regulator of ras in yeast.
PMID:7592647
Association of human Pur alpha with the retinoblastoma protein, Rb, regulates binding to the single-stranded DNA Pur alpha recognition element.
PMID:7651420
Characterization of a novel 350-kilodalton nuclear phosphoprotein that is specifically involved in mitotic-phase progression.
PMID:7664264
The nuclear tyrosine kinase Rak associates with the retinoblastoma protein pRb.
PMID:7791904
Interaction between the retinoblastoma protein and the oncoprotein MDM2.
PMID:7890747
Binding of an interferon-inducible protein (p202) to the retinoblastoma protein.
PMID:7923370
The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest.
PMID:8245034
Structural and functional characterization of the HPV16 E7 protein expressed in bacteria.
PMID:8288605
Identification of discrete structural domains in the retinoblastoma protein. Amino-terminal domain is required for its oligomerization.
PMID:8756624
Cyclin-binding motifs are essential for the function of p21CIP1.
PMID:9054499
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.
PMID:9067421
A DNA polymerase alpha accessory protein exhibits structural and functional similarities to SV40 large tumor antigen.
PMID:9395244
Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha.
PMID:9448006
The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein.
PMID:9468139
Retinoblastoma protein recruits histone deacetylase to repress transcription.
PMID:9468140
Retinoblastoma protein represses transcription by recruiting a histone deacetylase.
PMID:9608663
The rubella virus putative replicase interacts with the retinoblastoma tumor suppressor protein.
PMID:9697699
A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability.
PMID:9858607
Rb inhibits the intrinsic kinase activity of TATA-binding protein-associated factor TAFII250.
PMID:9881977
Direct suppression of Stat1 function during adenoviral infection.
Reactome:R-HSA-113503
PP2A mediated localization of RB1 protein in chromatin
Reactome:R-HSA-187948
Phosphorylation of proteins involved in the G1/S transition by Cyclin A:Cdk2
Reactome:R-HSA-188191
APC/C:Cdh1-mediated degradation of Skp2
Reactome:R-HSA-188386
Association of Rb with Cyclin E:Cdk2 complexes
Reactome:R-HSA-188390
Cyclin E:CDK2-mediated phosphorylation of RB1
Reactome:R-HSA-2172666
RB1 binds condensin II
Reactome:R-HSA-69227
Cyclin D:CDK4/6 phosphorylates RB1 and prevents RB1 binding to E2F1/2/3:DP1/2 complexes
Reactome:R-HSA-9018017
RB1 binds and inhibits E2F1/2/3:DP1/2 complexes
Reactome:R-HSA-9659782
Defective RB1 does not bind E2F1,(E2F2,E2F3)
Reactome:R-HSA-9659820
RB1 translocates to the nucleus
Reactome:R-HSA-9660615
Defective RB1 does not translocate to the nucleus
Reactome:R-HSA-9682712
nsp15 binds RB1
Reactome:R-HSA-9686969
APC/C:Cdh1 polyubiquitinates SKP2
Reactome:R-HSA-9686980
RB1 recruits APC/C:Cdh1 complex to SKP2
Reactome:R-HSA-9687377
Defective RB1 does not form a complex with SKP2 and FZR1
Reactome:R-HSA-9768288
RB1 and TFAP2A bind CDH1 gene promoter
Reactome:R-HSA-9851127
NPM1-ALK-dependent repression of pRB phosphorylation
Reactome:R-NUL-8985474
Runx2 binds RB1
Reactome:R-NUL-8985490
Runx2:RB1 binds the BGLAP gene promoter
file:human/RB1/RB1-deep-research-falcon.md
RB1 deep research (falcon, 2024 reviews synthesis)

Deep Research

Falcon

(RB1-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 38 citations 2026-05-07T21:22:04.301183

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human RB1 (UniProt P06400) — functional annotation of retinoblastoma‑associated protein (pRb)

0) Target verification (mandatory)

The UniProt accession P06400 corresponds to human RB1, encoding the retinoblastoma‑associated protein (pRb; also called p105‑Rb/p110‑RB1). Contemporary literature defines RB (pRb) as a nuclear, chromatin‑associated tumor suppressor transcriptional corepressor that restrains cell‑cycle progression primarily through E2F transcription factor repression and is regulated by cyclin–CDK phosphorylation (sanidas2024patternsinthe pages 3-4, wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4). This identity is consistent with RB family biology and with domain-function expectations for a pocket protein (lai2024mechanismsunderlyingsusceptibility pages 12-15).

1) Key concepts and definitions (current understanding)

1.1 Canonical function: RB–E2F gatekeeping of the G1/S transition

pRb’s primary function is to enforce the G1 restriction point by binding and repressing activator E2Fs (classically E2F1/2/3) and thereby suppressing transcriptional programs required for DNA replication and S‑phase entry (wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4, lai2024mechanismsunderlyingsusceptibility pages 12-15). A mechanistic definition emerging across recent reviews is that RB can repress E2F-dependent transcription both by masking E2F transactivation domains and by recruiting chromatin modifiers (sizer2024selectiveoccupationby pages 1-2).

Consistent with its role as a transcriptional corepressor rather than an enzyme/transporter, RB is described as a multi-partner scaffold (interaction resources list >300 partners, summarized in a 2024 analysis of RB occupancy and recruitment) (sizer2024selectiveoccupationby pages 1-2).

1.2 RB as a chromatin‑bound regulator (beyond “E2F only”)

A 2024 Trends in Cell Biology review emphasizes that RB is best conceptualized as a chromatin‑bound regulator with binding patterns that extend well beyond the relatively small sets of genes commonly used as “RB/E2F signatures” (sanidas2024patternsinthe pages 3-4, sanidas2024patternsinthe pages 6-8). Modern ChIP‑seq datasets show RB occupancy at thousands of loci, with promoter binding often strongest and enhancer binding extensive but context-dependent (sanidas2024patternsinthe pages 3-4, sanidas2024patternsinthe pages 6-8).

1.3 Post‑translational regulation: phosphorylation “states” as functional encodings

RB activity is classically regulated by cyclin–CDK phosphorylation, which weakens RB’s repression of E2F and allows cell-cycle progression (wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4). Recent syntheses stress RB exists in multiple phosphorylation isoforms, and that phosphorylation can do more than switch RB “off”: it can re-target RB to different chromatin environments (promoters vs enhancers) and modulate interaction partners (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6).

2) Recent developments and latest research (prioritizing 2023–2024)

2.1 A 2024 Nature model: a reversible intermediate Rb–E2F state (two-step phosphorylation)

Konagaya et al. (Nature, June 2024) provide a major mechanistic update: cells can occupy a reversible intermediate Rb–E2F activity state in G1 before committing to proliferation (konagaya2024anintermediaterb–e2f pages 1-2). This state is associated with preferential early phosphorylation at T373 (and S608) and a distinct later phase of cooperative hyperphosphorylation at C-terminal sites (S780, S807/S811, T826) that accompanies full E2F activation (konagaya2024anintermediaterb–e2f pages 4-5).

Key quantitative findings include:
- An initial ~5‑fold preference for phosphorylation at T373 over C‑terminal sites S807/S811 during early G1 (konagaya2024anintermediaterb–e2f pages 3-4).
- Cooperative, switch‑like phosphorylation behavior at S807/S811 (and related C-terminal sites), fit by a Hill coefficient 5.81 ± 0.44, consistent with ultrasensitivity (konagaya2024anintermediaterb–e2f pages 4-5).
- Phosphatase (PP1/PP2A) preference and kinetic asymmetry: combined phosphatases show 6.79 ± 2.15‑fold preference for dephosphorylating S807/S811 over T373, and T373 dephosphorylation is 6.65 ± 1.05‑fold slower than S807/S811 (konagaya2024anintermediaterb–e2f pages 6-7).

Mechanistically, the authors propose that T373‑phosphorylated RB remains chromatin-bound in the intermediate state, whereas broader hyperphosphorylation is associated with full E2F release (konagaya2024anintermediaterb–e2f pages 1-2).

Supporting figure evidence (from the paper): Figure 3 schematizes the two-step phosphorylation program and maps early versus late phosphorylation sites onto RB domain architecture (konagaya2024anintermediaterb–e2f media 5282880f, konagaya2024anintermediaterb–e2f media 04227eec).

2.2 2024 expert synthesis: RB chromatin binding is patterned across promoters, enhancers, and CTCF sites

Sanidas et al. (Trends Cell Biol, April 2024) synthesize evidence that RB binding occurs at promoters, enhancers, and CTCF-bound loci, and that RB’s chromatin association is not restricted to a single “E2F promoter repression” mode (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6). Quantitatively, they report promoter binding is comparatively conserved between cell types (>70% conserved in an example comparison) whereas enhancer binding is much more cell-type specific (~11% conserved), implying recruitment mechanisms and function differ by chromatin context (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6).

They also highlight emerging evidence that hyperphosphorylated RB can be found at enhancers in cycling cells and correlate with increased H3K27ac, while “active” (unphosphorylated/mono‑phosphorylated) RB tends to associate with promoters and reduced H3K27ac—supporting a multi-state model rather than a binary on/off chromatin-binding model (sanidas2024patternsinthe pages 4-6).

2.3 2024 analyses expand transcriptional scope: selective regulation of RNA polymerase III output

Sizer et al. (Cancers, January 2024) discuss RB as a regulator of RNA polymerase III (Pol III) transcription, classically via binding TFIIIB and suppressing Pol III initiation, and also via E2F-dependent recruitment of RB to subsets of Pol III loci (tRNA genes and other Pol III transcripts) (sizer2024selectiveoccupationby pages 1-2). They summarize functional assays in which serum withdrawal caused an approximately two-fold decrease in tRNA synthesis in Rb+/+ MEFs that was absent in Rb−/− MEFs, supporting a direct RB requirement for this repression in that model system (sizer2024selectiveoccupationby pages 1-2).

3) Biological processes, pathways, and interaction networks (mechanistic focus)

3.1 Core pathway: Cyclin–CDK → RB phosphorylation → E2F activation

Recent reviews explicitly list cyclin–CDK complexes that phosphorylate RB and relieve E2F repression, including Cyclin D–CDK4/6, Cyclin E–CDK2, and (in some contexts) Cyclin C–CDK3 (huang2024therapeuticstrategiesfor pages 2-4). The 2024 Nature work refines this into a signal-integration logic: RB can integrate inputs from CDK4/6 and CDK2 through site-specific phosphorylation before full commitment to proliferation (konagaya2024anintermediaterb–e2f pages 1-2, konagaya2024anintermediaterb–e2f pages 4-5).

3.2 Chromatin repression machinery and recruitment mechanisms

RB-mediated repression is supported by recruitment of chromatin modifiers, including HDACs, DNA methyltransferases, and SUV39H1 (heterochromatin-associated H3K9 methyltransferase), providing a mechanistic bridge between RB–E2F binding and durable transcriptional silencing (sizer2024selectiveoccupationby pages 1-2). Sanidas et al. further emphasize that promoter/enhancer RB recruitment can involve distinct transcription factors such as E2F1 at promoters and cJun/AP‑1 at enhancers, and can vary substantially by cell type and cellular state (sanidas2024patternsinthe pages 4-6).

3.3 Genome stability and DNA repair pathways

RB is repeatedly characterized as contributing to genome integrity, including through roles in double-strand break repair. A 2024 cancer-focused review notes RB necessity in canonical non‑homologous end joining (cNHEJ) and specifies interaction with NHEJ components XRCC5 (Ku80) and XRCC6 (Ku70) (huang2024therapeuticstrategiesfor pages 2-4). A separate 2024 review also summarizes RB participation in DNA damage response and repair, including interactions with Ku70/Ku80 for NHEJ and recruitment of chromatin remodeling activities (e.g., BRG1) for homologous recombination-associated repair programs (wang2024thesignificanceof pages 2-4).

3.4 Differentiation, senescence, and lineage fidelity

Expert synthesis in 2024 emphasizes RB’s tumor-suppressive roles extend to promotion of differentiation, triggering senescence, maintenance of lineage fidelity, and chromatin organization, suggesting that RB loss drives cancer not only by increasing proliferation but also by reshaping cell identity programs (sanidas2024patternsinthe pages 3-4, sanidas2024patternsinthe pages 4-6). Reviews also highlight RB functioning as a transcriptional cofactor with non‑E2F transcription factors (e.g., CEBPD, PU.1, androgen receptor), expanding the set of pathways RB can modulate beyond canonical cell-cycle genes (huang2024therapeuticstrategiesfor pages 2-4).

4) Subcellular localization and where RB1 acts

Across authoritative 2024 sources, RB is described as predominantly nuclear and chromatin-associated, consistent with its role as a transcriptional regulator and chromatin organizer (sanidas2024patternsinthe pages 3-4, wang2024thesignificanceof pages 2-4). Its localization is dynamic in the sense of chromatin targeting: RB occupancy is seen at promoters, enhancers, and CTCF-bound loci and can redistribute with cell cycle and phosphorylation state (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6). The 2024 Nature work further refines this by suggesting that during a “primed” intermediate state, T373‑phosphorylated RB remains chromatin-bound, whereas broader hyperphosphorylation is associated with the transition to full E2F activation (konagaya2024anintermediaterb–e2f pages 1-2).

5) Current applications and real‑world implementations (clinical/translational)

5.1 RB1 status as a biomarker in CDK4/6 inhibitor therapy (breast cancer)

RB1 functional loss is a clinically observed mechanism of resistance to CDK4/6 inhibitors in ER+/HER2− metastatic breast cancer. A 2023 longitudinal multi‑omics cohort study reports frequencies of RB1 alterations after treatment across studies and within their own cohort:
- PALOMA‑3: RB1 mutations in 4.7% of patients treated with palbociclib + fulvestrant (as cited in the 2023 analysis) (park2023longitudinalmultiomicsstudy pages 14-15).
- Another WES resistant-tumor series: RB1 loss-of-function in 9.8% of resistant tumors (park2023longitudinalmultiomicsstudy pages 14-15).
- In the authors’ paired progression cohort: acquired RB1 loss-of-function in 19% of paired post‑progression tumors (park2023longitudinalmultiomicsstudy pages 14-15).

This supports RB1 loss as a treatment-emergent resistance mechanism and motivates RB1/functional pRb assessment in biomarker strategies (park2023longitudinalmultiomicsstudy pages 14-15).

A 2024 real‑world retrospective analysis of 195 ER+/HER2− metastatic breast cancer patients evaluated CDK4/6 inhibitor retrial and reported median time-to-treatment-failure (TTF) outcomes; RB1 loss-of-function mutations were among candidate genomic features associated with retrial failure (mai2024predictorsofresponse pages 1-2).

5.2 RB phosphorylation (functional state) as an actionable biomarker and synthetic-lethality lever (rectal cancer)

Yu et al. (PNAS, January 2024) describe a clinically oriented implementation concept: phosphorylated RB1 (p‑RB1, S780) is associated with resistance to oxaliplatin-based neoadjuvant chemotherapy in locally advanced rectal cancer (yu2024pharmacologicalmodulationof pages 1-2). They report:
- p‑RB1 as a predictor of nonresponse with AUC = 0.85 (yu2024pharmacologicalmodulationof pages 5-5).
- IHC cohort sizes: responders n=32, nonresponders n=40, and paired primary/relapse samples n=27 (yu2024pharmacologicalmodulationof pages 5-5).
- Context statistic: only 5–10% of LARC is MMR-deficient, while 30–60% of MMR-proficient cases are resistant to neoadjuvant chemotherapy (yu2024pharmacologicalmodulationof pages 1-2).

Mechanistically, they propose CDK4/6 inhibition antagonizes RB1 phosphorylation and enforces RB1/TEAD4/HDAC1 function to induce DNA repair defects that sensitize oxaliplatin, framing a biomarker-guided combination strategy (yu2024pharmacologicalmodulationof pages 1-2).

5.3 Therapeutic strategies for RB1-deficient cancers (synthetic vulnerabilities)

A 2024 review highlights that RB1 loss creates therapeutic vulnerabilities exploitable by targeted approaches, including synthetic-lethal relationships (e.g., PRMT5-related vulnerabilities in ER+/RB1-deficient contexts) and epigenetic dependencies, providing an expert roadmap for translational development in RB1-deficient tumors (huang2024therapeuticstrategiesfor pages 10-12, huang2024therapeuticstrategiesfor pages 9-10).

6) Disease association and recent statistics (retinoblastoma and survivorship)

6.1 Germline RB1 variants in unilateral retinoblastoma (2024 cohort)

A 2024 cohort study of 50 unilateral retinoblastoma cases reported germline RB1 pathogenic variants in 14/50 (28%) overall and 11/47 (23%) among unilateral non‑familial cases (yousef2024mutationalanalysisof pages 1-2). Outcomes at median 54 months follow-up included 2/50 (4%) deaths from distant metastasis and an overall eye salvage rate of 44% (22/50); germline mutation presence did not correlate with eye salvage, metastasis, or survival in that cohort (yousef2024mutationalanalysisof pages 1-2).

6.2 Parent-of-origin effect and chemotherapy failure risk (2024 JCI Insight)

A 2024 study leveraging long-read genome/epigenome sequencing and an RB1 intron-2 differentially methylated region reported that pathogenic variants on the paternally inherited allele were associated with more advanced staging at presentation and a significantly greater risk of chemotherapy failure (P = 0.002) (stacey2024prognosticimportanceof pages 1-2). The same report notes that in heritable retinoblastoma, >90% of germline cases are de novo (stacey2024prognosticimportanceof pages 1-2).

6.3 Second primary cancer risk in survivors (2024 meta-analysis)

A 2024 systematic review/meta-analysis (10 studies) quantified elevated second primary cancer risk in hereditary retinoblastoma: pooled SIR = 17.55 (95% CI 13.10–23.51) versus nonhereditary pooled SIR = 1.36 (95% CI 0.90–2.04) (sun2024incidenceofsecond pages 1-2). Very high site-specific SIRs were reported for nasal cavity tumors (591.06), bone tumors (442.91), and soft tissue sarcoma (202.93), with elevated risks for CNS tumors (12.84) and female breast cancer (3.68) (sun2024incidenceofsecond pages 1-2). These data underpin current survivorship surveillance concerns and risk counseling in germline RB1 carriers.

6.4 Database corroboration (Open Targets)

Open Targets reports a strong disease–target association between RB1 and retinoblastoma, including hereditary and nonhereditary forms, supporting RB1 as the dominant causal gene in this disease class at a knowledge-graph level (sun2024incidenceofsecond pages 1-2).

7) Expert interpretation and synthesis (authoritative viewpoints)

A central 2024 expert theme is that RB should be treated as a multi-modal chromatin-bound regulator rather than a single-purpose E2F repressor. Sanidas et al. highlight that RB binds promoters and enhancers with context-specific patterns and that phosphorylation can correlate with different chromatin localizations and histone marks (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6). This repositions RB’s “inactive phosphorylated form” from being merely absent from chromatin to being potentially re-deployed at enhancers, implying different regulatory outputs.

Konagaya et al. provide a complementary mechanistic explanation for how RB can buffer noisy proliferative signals: slow-turnover central-site phosphorylation (T373) creates an intermediate state that can be reversed, delaying commitment until late G1 when cooperative hyperphosphorylation triggers full E2F activation (konagaya2024anintermediaterb–e2f pages 6-7, konagaya2024anintermediaterb–e2f pages 4-5). This modernizes the restriction point concept by adding a measurable primed intermediate state.

8) Summary for functional annotation (concise)

  • Primary molecular role: transcriptional corepressor that restrains G1/S progression by inhibiting E2F-driven transcription (wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4).
  • Regulation: multi-site phosphorylation by cyclin–CDK complexes controls repression strength and chromatin targeting; 2024 evidence supports a two-step program centered on early T373/S608 phosphorylation and later cooperative C-terminal hyperphosphorylation (konagaya2024anintermediaterb–e2f pages 4-5, konagaya2024anintermediaterb–e2f pages 3-4, sanidas2024patternsinthe pages 4-6).
  • Localization: predominantly nuclear and chromatin-bound, dynamically redistributed across promoters/enhancers/CTCF sites (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6).
  • Non-canonical mechanisms: chromatin organization and genome integrity roles; repression of Pol III transcription via TFIIIB and selective occupancy at Pol III loci; DNA repair interactions including Ku70/Ku80 and NHEJ components XRCC5/XRCC6 (sizer2024selectiveoccupationby pages 1-2, wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4).
  • Clinical relevance: RB1 loss or functional inactivation is a major theme in cancer therapy resistance (e.g., CDK4/6i resistance) and in hereditary cancer risk; pRB phosphorylation state can be developed as a biomarker in at least some contexts (p‑RB1 AUC 0.85 in 2024 LARC study) (park2023longitudinalmultiomicsstudy pages 14-15, yu2024pharmacologicalmodulationof pages 5-5, sun2024incidenceofsecond pages 1-2).

Reference summary (URLs and publication dates)

  • Konagaya et al. Nature (Jun 2024): https://doi.org/10.1038/s41586-024-07554-2 (konagaya2024anintermediaterb–e2f pages 1-2)
  • Sanidas et al. Trends in Cell Biology (Apr 2024): https://doi.org/10.1016/j.tcb.2023.07.012 (sanidas2024patternsinthe pages 3-4)
  • Huang et al. Cancers (Apr 2024): https://doi.org/10.3390/cancers16081558 (huang2024therapeuticstrategiesfor pages 2-4)
  • Sizer et al. Cancers (Jan 2024): https://doi.org/10.3390/cancers16030481 (sizer2024selectiveoccupationby pages 1-2)
  • Yu et al. PNAS (Jan 2024): https://doi.org/10.1073/pnas.2304619121 (yu2024pharmacologicalmodulationof pages 1-2)
  • Park et al. Genome Medicine (Jul 2023): https://doi.org/10.1186/s13073-023-01201-7 (park2023longitudinalmultiomicsstudy pages 14-15)
  • Mai et al. NPJ Breast Cancer (Oct 2024): https://doi.org/10.1038/s41523-024-00699-3 (mai2024predictorsofresponse pages 1-2)
  • Yousef et al. Frontiers in Medicine (Aug 2024): https://doi.org/10.3389/fmed.2024.1406215 (yousef2024mutationalanalysisof pages 1-2)
  • Stacey et al. JCI Insight (Dec 2024): https://doi.org/10.1172/jci.insight.188216 (stacey2024prognosticimportanceof pages 1-2)
  • Sun et al. Frontiers in Oncology (Mar 2024): https://doi.org/10.3389/fonc.2024.1372548 (sun2024incidenceofsecond pages 1-2)

Compact summary table

The following table consolidates core functions, regulation, localization, and translational relevance with quantitative findings where available:

Category Specific details (mechanism, partners, localization) Key recent evidence (2023-2024) with quantitative/statistical data when available
Definition / identity Human RB1 (UniProt P06400) encodes the retinoblastoma-associated protein (pRb/RB), a tumor suppressor transcriptional corepressor in the RB family. It is primarily nuclear and chromatin-associated, not an enzyme or transporter. Core activity is repression of proliferation-linked transcription through binding E2F/DP complexes. (sanidas2024patternsinthe pages 3-4, wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4) Recent reviews consistently define RB as a multifunctional chromatin-bound suppressor whose canonical role is G1/S control via E2F repression, while also noting broader functions in differentiation, senescence, and genome integrity. ChIP-seq studies detect RB at thousands of genomic loci, strongest at promoters but also at enhancers/CTCF sites. (sanidas2024patternsinthe pages 3-4, sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6)
Canonical molecular function pRb binds activator E2Fs (especially E2F1/2/3), masks transactivation domains, and recruits corepressors/chromatin modifiers including HDACs, DNA methyltransferases, and SUV39H1 to repress genes needed for DNA synthesis and S-phase entry. (sizer2024selectiveoccupationby pages 1-2, huang2024therapeuticstrategiesfor pages 2-4, lai2024mechanismsunderlyingsusceptibility pages 12-15) 2024 reviews emphasize that RB1 can arrest cells in G1 by inhibiting E2F1/2/3; loss of RB1 derepresses cell-cycle and DNA replication genes. This remains the best-supported primary function for human pRb. (sanidas2024patternsinthe pages 4-6, huang2024therapeuticstrategiesfor pages 2-4)
Regulation by Cyclin/CDK phosphorylation RB activity is switched by phosphorylation from Cyclin D–CDK4/6, Cyclin E–CDK2, and in some contexts Cyclin C–CDK3. Hypophosphorylated/mono-phosphorylated RB is growth suppressive; hyperphosphorylation weakens E2F repression and permits cell-cycle progression. (sizer2024selectiveoccupationby pages 1-2, wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4) A 2024 Nature study identified a reversible intermediate Rb–E2F state: early phosphorylation at T373 and S608 partially inactivates RB while remaining chromatin-bound; later cooperative phosphorylation at S780, S807/S811, T826 drives full E2F activation. Quantitatively, S807/S811 hyperphosphorylation showed a Hill coefficient 5.81 ± 0.44; phosphatases dephosphorylated S807/S811 ~6.79 ± 2.15-fold more readily than T373, and T373 dephosphorylation was 6.65 ± 1.05-fold slower. (konagaya2024anintermediaterb–e2f pages 6-7, konagaya2024anintermediaterb–e2f pages 1-2, konagaya2024anintermediaterb–e2f pages 4-5, konagaya2024anintermediaterb–e2f pages 3-4)
Chromatin binding and genomic organization RB is dynamically recruited to promoters, enhancers, and CTCF-bound loci through transcription factors such as E2F1 and cJun/AP-1. Beyond direct promoter repression, RB influences chromatin state, enhancer activity, and large-scale chromosome structure. (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6) Promoter binding is relatively conserved across cell types, whereas enhancer binding is highly context-specific. A 2024 review reports >70% conservation of promoter RB-binding sites between two cell types but only ~11% conservation at enhancers; cluster analysis suggested up to ~50 RB-binding categories. Hyperphosphorylated RB was associated with enhancer localization and increased H3K27ac, whereas active RB associated with promoters and reduced H3K27ac. (sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6)
Non-canonical transcriptional roles RB also represses RNA polymerase III output by binding TFIIIB and can be recruited near specific pol III loci by E2Fs, allowing selective control of tRNAs, 5S rRNA, RMRP, RN7SL and related noncoding RNAs. Localization remains nuclear/chromatin-associated. (sizer2024selectiveoccupationby pages 1-2) Nuclear run-on evidence summarized in 2024 showed endogenous RB suppresses tRNA and 5S rRNA synthesis; serum withdrawal caused an approximately 2-fold decrease in tRNA synthesis in Rb+/+ MEFs that was lost in Rb−/− MEFs, supporting direct regulation of growth-related noncoding RNA synthesis. (sizer2024selectiveoccupationby pages 1-2)
DNA damage repair / genome maintenance RB supports genome integrity through roles in double-strand break repair and chromatin maintenance. Reported partners include XRCC5/Ku80, XRCC6/Ku70 for canonical NHEJ, and BRG1 in homologous recombination-related responses; RB also contributes to heterochromatin, telomere stability, centromere structure, and chromosome condensation via Condensin II-linked functions. (wang2024thesignificanceof pages 2-4, sanidas2024patternsinthe pages 4-6, huang2024therapeuticstrategiesfor pages 2-4) 2024 reviews describe RB as necessary for cNHEJ and broader genome-stability programs, extending functional annotation beyond transcriptional repression alone. These roles help explain why RB loss promotes genomic instability in cancer. (wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4)
Senescence, differentiation, lineage fidelity RB promotes cellular senescence, differentiation, and maintenance of lineage identity; it can function with non-E2F transcription factors such as CEBPD, PU.1, and androgen receptor to regulate lineage-specific programs. (sanidas2024patternsinthe pages 3-4, sanidas2024patternsinthe pages 9-11, huang2024therapeuticstrategiesfor pages 2-4, lai2024mechanismsunderlyingsusceptibility pages 12-15) Recent expert analysis argues RB’s tumor-suppressive action is not limited to cell-cycle arrest but includes preserving differentiation state and chromatin organization. Reduced compensation by p130 in senescence may make RB-specific chromatin programs especially important in durable growth arrest. (sanidas2024patternsinthe pages 3-4, sanidas2024patternsinthe pages 4-6)
Subcellular localization Functional pRb is predominantly nuclear and chromatin-bound. Its chromatin occupancy changes with cell-cycle state and phosphorylation: active RB is promoter-enriched in quiescent/arrested cells; phosphorylated RB can redistribute to enhancers in cycling cells. (sanidas2024patternsinthe pages 3-4, sanidas2024patternsinthe pages 6-8, sanidas2024patternsinthe pages 4-6) 2024 work showed T373-phosphorylated RB can remain chromatin-bound during the intermediate state, whereas later hyperphosphorylation is associated with dissociation from E2F repression and broader redistribution. This refines the older simple on/off model. (konagaya2024anintermediaterb–e2f pages 6-7, konagaya2024anintermediaterb–e2f pages 1-2, sanidas2024patternsinthe pages 4-6)
Core pathways Central pathway: Cyclin D/CDK4/6–RB–E2F G1 restriction point. Additional connected pathways include chromatin remodeling, DNA repair, apoptosis/metabolism through E2F targets, and selective repression of Pol III transcription. (sizer2024selectiveoccupationby pages 1-2, wang2024thesignificanceof pages 2-4, huang2024therapeuticstrategiesfor pages 2-4) A 2024 Nature study supports a two-step pathway model in which RB integrates CDK4/6 and CDK2 signals before commitment to proliferation; simultaneous inhibition of CDK2 + CDK4/6 was needed to fully block E2F activation in that system. (konagaya2024anintermediaterb–e2f pages 1-2, konagaya2024anintermediaterb–e2f pages 4-5)
Clinical application: biomarker for CDK4/6 inhibitor response Functional RB is generally required for benefit from CDK4/6 inhibitors; RB1 loss-of-function is a recurrent mechanism of resistance in HR+/HER2− metastatic breast cancer and is being explored as a predictive biomarker. (park2023longitudinalmultiomicsstudy pages 14-15, huang2024therapeuticstrategiesfor pages 10-12, mai2024predictorsofresponse pages 1-2) In a 2023 longitudinal multi-omics study, acquired RB1 LOF was found in 19% of paired post-progression tumors after palbociclib + endocrine therapy, versus prior reports of 4.7% (PALOMA-3) and 9.8% in another resistant-tumor WES series. A 2024 real-world retrial cohort (n=195) found RB1 LOF among candidate biomarkers of CDK4/6 retrial failure; median TTF was 10.1 months after toxicity-related retreatment and 4.3 vs 4.7 months for same vs different CDK4/6i after prior progression. (park2023longitudinalmultiomicsstudy pages 14-15, mai2024predictorsofresponse pages 1-2)
Clinical application: synthetic lethal / combination strategies RB1-deficient tumors may be vulnerable to PRMT5, SKP2, LSD1, and other synthetic-lethal or pathway-compensatory approaches; in RB1-proficient settings, pharmacologic maintenance of RB activity can sensitize tumors to therapy. (huang2024therapeuticstrategiesfor pages 10-12, huang2024therapeuticstrategiesfor pages 9-10) 2024 review evidence highlights PRMT5 inhibition as a synthetic vulnerability in ER+/RB1-deficient models and notes selective anti-retinoblastoma effects of SKP2-axis targeting. In rectal cancer, CDK4/6 inhibition reduced RB1 phosphorylation and sensitized oxaliplatin-resistant disease. (huang2024therapeuticstrategiesfor pages 10-12, yu2024pharmacologicalmodulationof pages 1-2, huang2024therapeuticstrategiesfor pages 9-10)
Real-world implementation beyond breast cancer RB phosphorylation state, not just RB1 mutation, can be clinically actionable. In locally advanced rectal cancer (LARC), phosphorylated RB1 was linked to oxaliplatin resistance, suggesting a biomarker-guided combination approach. (yu2024pharmacologicalmodulationof pages 1-2, yu2024pharmacologicalmodulationof pages 5-5) In a 2024 PNAS study, p-RB1 (S780) predicted nonresponse to neoadjuvant therapy with AUC = 0.85; cohorts included responders n=32, nonresponders n=40, and paired primary/relapse samples n=27. The study notes only 5–10% of LARC is MMR-deficient, while 30–60% of MMR-proficient cases resist neoadjuvant chemotherapy, supporting RB-directed sensitization strategies. (yu2024pharmacologicalmodulationof pages 1-2, yu2024pharmacologicalmodulationof pages 5-5)
Disease association: hereditary retinoblastoma Germline RB1 mutation predisposes to hereditary retinoblastoma; disease is classically high penetrance, often de novo, and associated with lifelong second-cancer risk. Open Targets also lists strong target–disease association for retinoblastoma and hereditary retinoblastoma. (stacey2024prognosticimportanceof pages 1-2, sun2024incidenceofsecond pages 1-2) A 2024 study states >90% of heritable germline cases are de novo and found that paternally inherited pathogenic alleles were associated with more advanced presentation and greater chemotherapy failure risk (P = 0.002). A 2024 unilateral retinoblastoma cohort found germline RB1 variants in 14/50 (28%) overall and 11/47 (23%) of unilateral non-familial cases. (yousef2024mutationalanalysisof pages 1-2, stacey2024prognosticimportanceof pages 1-2, sun2024incidenceofsecond pages 1-2)
Disease association: survivor risk statistics Hereditary RB1 mutation carriers are at markedly increased risk of second primary cancers, particularly sarcoma and selected epithelial tumors; treatment can further increase risk. (sun2024incidenceofsecond pages 1-2) A 2024 meta-analysis of 10 studies reported pooled standardized incidence ratio (SIR) for second primary cancers of 17.55 (95% CI 13.10–23.51) in hereditary retinoblastoma versus 1.36 (95% CI 0.90–2.04) in nonhereditary disease. Site-specific SIRs were extremely high for nasal cavity tumors 591.06, bone tumors 442.91, soft-tissue sarcoma 202.93, with elevated CNS tumors 12.84 and female breast cancer 3.68. (sun2024incidenceofsecond pages 1-2)

Table: This table summarizes the molecular functions, pathways, localization, and clinical relevance of human RB1/pRb, emphasizing 2023-2024 evidence and quantitative findings. It is designed as a compact reference for functional annotation and translational interpretation.

References

  1. (sanidas2024patternsinthe pages 3-4): Ioannis Sanidas, Michael S. Lawrence, and Nicholas J. Dyson. Patterns in the tapestry of chromatin-bound rb. Trends in Cell Biology, 34:288-298, Apr 2024. URL: https://doi.org/10.1016/j.tcb.2023.07.012, doi:10.1016/j.tcb.2023.07.012. This article has 19 citations and is from a domain leading peer-reviewed journal.

  2. (wang2024thesignificanceof pages 2-4): Yiwen Wang, Rui Yang, Rui Liu, Ruoyu Yang, Zujie Lin, and Aili He. The significance of rb1 in multiple myeloma. Frontiers in Immunology, Nov 2024. URL: https://doi.org/10.3389/fimmu.2024.1415972, doi:10.3389/fimmu.2024.1415972. This article has 5 citations and is from a peer-reviewed journal.

  3. (huang2024therapeuticstrategiesfor pages 2-4): Mo-Fan Huang, Yuan-Xin Wang, Yu-Ting Chou, and Dung-Fang Lee. Therapeutic strategies for rb1-deficient cancers: intersecting gene regulation and targeted therapy. Cancers, 16:1558, Apr 2024. URL: https://doi.org/10.3390/cancers16081558, doi:10.3390/cancers16081558. This article has 27 citations.

  4. (lai2024mechanismsunderlyingsusceptibility pages 12-15): CCH Lai. Mechanisms underlying susceptibility to cancer initiation or lineage-switching in established cancer. Unknown journal, 2024.

  5. (sizer2024selectiveoccupationby pages 1-2): Rebecca E Sizer, Sienna P Butterfield, Lucy A. Hancocks, Leonor Gato De Sousa, and Robert J. White. Selective occupation by e2f and rb of loci expressed by rna polymerase iii. Cancers, 16:481, Jan 2024. URL: https://doi.org/10.3390/cancers16030481, doi:10.3390/cancers16030481. This article has 1 citations.

  6. (sanidas2024patternsinthe pages 6-8): Ioannis Sanidas, Michael S. Lawrence, and Nicholas J. Dyson. Patterns in the tapestry of chromatin-bound rb. Trends in Cell Biology, 34:288-298, Apr 2024. URL: https://doi.org/10.1016/j.tcb.2023.07.012, doi:10.1016/j.tcb.2023.07.012. This article has 19 citations and is from a domain leading peer-reviewed journal.

  7. (sanidas2024patternsinthe pages 4-6): Ioannis Sanidas, Michael S. Lawrence, and Nicholas J. Dyson. Patterns in the tapestry of chromatin-bound rb. Trends in Cell Biology, 34:288-298, Apr 2024. URL: https://doi.org/10.1016/j.tcb.2023.07.012, doi:10.1016/j.tcb.2023.07.012. This article has 19 citations and is from a domain leading peer-reviewed journal.

  8. (konagaya2024anintermediaterb–e2f pages 1-2): Yumi Konagaya, David L Rosenthal, Nalin Ratnayeke, Yilin Fan, and Tobias Meyer. An intermediate rb–e2f activity state safeguards proliferation commitment. Nature, 631:424-431, Jun 2024. URL: https://doi.org/10.1038/s41586-024-07554-2, doi:10.1038/s41586-024-07554-2. This article has 57 citations and is from a highest quality peer-reviewed journal.

  9. (konagaya2024anintermediaterb–e2f pages 4-5): Yumi Konagaya, David L Rosenthal, Nalin Ratnayeke, Yilin Fan, and Tobias Meyer. An intermediate rb–e2f activity state safeguards proliferation commitment. Nature, 631:424-431, Jun 2024. URL: https://doi.org/10.1038/s41586-024-07554-2, doi:10.1038/s41586-024-07554-2. This article has 57 citations and is from a highest quality peer-reviewed journal.

  10. (konagaya2024anintermediaterb–e2f pages 3-4): Yumi Konagaya, David L Rosenthal, Nalin Ratnayeke, Yilin Fan, and Tobias Meyer. An intermediate rb–e2f activity state safeguards proliferation commitment. Nature, 631:424-431, Jun 2024. URL: https://doi.org/10.1038/s41586-024-07554-2, doi:10.1038/s41586-024-07554-2. This article has 57 citations and is from a highest quality peer-reviewed journal.

  11. (konagaya2024anintermediaterb–e2f pages 6-7): Yumi Konagaya, David L Rosenthal, Nalin Ratnayeke, Yilin Fan, and Tobias Meyer. An intermediate rb–e2f activity state safeguards proliferation commitment. Nature, 631:424-431, Jun 2024. URL: https://doi.org/10.1038/s41586-024-07554-2, doi:10.1038/s41586-024-07554-2. This article has 57 citations and is from a highest quality peer-reviewed journal.

  12. (konagaya2024anintermediaterb–e2f media 5282880f): Yumi Konagaya, David L Rosenthal, Nalin Ratnayeke, Yilin Fan, and Tobias Meyer. An intermediate rb–e2f activity state safeguards proliferation commitment. Nature, 631:424-431, Jun 2024. URL: https://doi.org/10.1038/s41586-024-07554-2, doi:10.1038/s41586-024-07554-2. This article has 57 citations and is from a highest quality peer-reviewed journal.

  13. (konagaya2024anintermediaterb–e2f media 04227eec): Yumi Konagaya, David L Rosenthal, Nalin Ratnayeke, Yilin Fan, and Tobias Meyer. An intermediate rb–e2f activity state safeguards proliferation commitment. Nature, 631:424-431, Jun 2024. URL: https://doi.org/10.1038/s41586-024-07554-2, doi:10.1038/s41586-024-07554-2. This article has 57 citations and is from a highest quality peer-reviewed journal.

  14. (park2023longitudinalmultiomicsstudy pages 14-15): Yeon Hee Park, Seock-Ah Im, Kyunghee Park, Ji Wen, Kyung-Hun Lee, Yoon-La Choi, Won-Chul Lee, Ahrum Min, Vinicius Bonato, Seri Park, Sripad Ram, Dae-Won Lee, Ji-Yeon Kim, Su Kyeong Lee, Won-Woo Lee, Jisook Lee, Miso Kim, Hyun Seon Kim, Scott L. Weinrich, Han Suk Ryu, Tae Yong Kim, Stephen Dann, Yu-Jin Kim, Diane R. Fernandez, Jiwon Koh, Shuoguo Wang, Song Yi Park, Shibing Deng, Eric Powell, Rupesh Kanchi Ravi, Jadwiga Bienkowska, Paul A. Rejto, Woong-Yang Park, and Zhengyan Kan. Longitudinal multi-omics study of palbociclib resistance in hr-positive/her2-negative metastatic breast cancer. Genome Medicine, Jul 2023. URL: https://doi.org/10.1186/s13073-023-01201-7, doi:10.1186/s13073-023-01201-7. This article has 59 citations and is from a highest quality peer-reviewed journal.

  15. (mai2024predictorsofresponse pages 1-2): Nicholas Mai, Carlos H. dos Anjos, Pedram Razavi, Anton Safonov, Sujata Patil, Yuan Chen, Joshua Z. Drago, Shanu Modi, Jacqueline F. Bromberg, Chau T. Dang, Dazhi Liu, Larry Norton, Mark Robson, Sarat Chandarlapaty, and Komal Jhaveri. Predictors of response to cdk4/6i retrial after prior cdk4/6i failure in er+ metastatic breast cancer. NPJ Breast Cancer, Oct 2024. URL: https://doi.org/10.1038/s41523-024-00699-3, doi:10.1038/s41523-024-00699-3. This article has 8 citations and is from a peer-reviewed journal.

  16. (yu2024pharmacologicalmodulationof pages 1-2): Zhaoliang Yu, Peng Deng, Yufeng Chen, Dezheng Lin, Shini Liu, Jinghan Hong, Peiyong Guan, Jianfeng Chen, Min-er Zhong, Jinghong Chen, Xiaochuan Chen, Yichen Sun, Yali Wang, Peili Wang, Zerong Cai, Jason Yongsheng Chan, Yulin Huang, Rong Xiao, Yaoyu Guo, Xian Zeng, Wenyu Wang, Yifeng Zou, Qiang Yu, Ping Lan, Bin Tean Teh, Xiaojian Wu, and Jing Tan. Pharmacological modulation of rb1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer. Proceedings of the National Academy of Sciences of the United States of America, Jan 2024. URL: https://doi.org/10.1073/pnas.2304619121, doi:10.1073/pnas.2304619121. This article has 19 citations and is from a highest quality peer-reviewed journal.

  17. (yu2024pharmacologicalmodulationof pages 5-5): Zhaoliang Yu, Peng Deng, Yufeng Chen, Dezheng Lin, Shini Liu, Jinghan Hong, Peiyong Guan, Jianfeng Chen, Min-er Zhong, Jinghong Chen, Xiaochuan Chen, Yichen Sun, Yali Wang, Peili Wang, Zerong Cai, Jason Yongsheng Chan, Yulin Huang, Rong Xiao, Yaoyu Guo, Xian Zeng, Wenyu Wang, Yifeng Zou, Qiang Yu, Ping Lan, Bin Tean Teh, Xiaojian Wu, and Jing Tan. Pharmacological modulation of rb1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer. Proceedings of the National Academy of Sciences of the United States of America, Jan 2024. URL: https://doi.org/10.1073/pnas.2304619121, doi:10.1073/pnas.2304619121. This article has 19 citations and is from a highest quality peer-reviewed journal.

  18. (huang2024therapeuticstrategiesfor pages 10-12): Mo-Fan Huang, Yuan-Xin Wang, Yu-Ting Chou, and Dung-Fang Lee. Therapeutic strategies for rb1-deficient cancers: intersecting gene regulation and targeted therapy. Cancers, 16:1558, Apr 2024. URL: https://doi.org/10.3390/cancers16081558, doi:10.3390/cancers16081558. This article has 27 citations.

  19. (huang2024therapeuticstrategiesfor pages 9-10): Mo-Fan Huang, Yuan-Xin Wang, Yu-Ting Chou, and Dung-Fang Lee. Therapeutic strategies for rb1-deficient cancers: intersecting gene regulation and targeted therapy. Cancers, 16:1558, Apr 2024. URL: https://doi.org/10.3390/cancers16081558, doi:10.3390/cancers16081558. This article has 27 citations.

  20. (yousef2024mutationalanalysisof pages 1-2): Yacoub A. Yousef, Mona Mohammad, Laith Baqain, Maysa Al-Hussaini, Mayada Abu Shanap, Hadeel Halalsheh, Jakub Khzouz, Imad Jaradat, Mustafa Mehyar, Iyad Sultan, Ibrahim AlNawaiseh, and Munir Shawagfeh. Mutational analysis of the rb1 gene in patients with unilateral retinoblastoma. Frontiers in Medicine, Aug 2024. URL: https://doi.org/10.3389/fmed.2024.1406215, doi:10.3389/fmed.2024.1406215. This article has 2 citations.

  21. (stacey2024prognosticimportanceof pages 1-2): Andrew W. Stacey, Kenji Nakamichi, Jennifer Huey, Jeffrey Stevens, Natalie Waligorski, Erin E. Crotty, Russell N. Van Gelder, and Debarshi Mustafi. Prognostic importance of direct assignment of parent of origin via long-read genome and epigenome sequencing in retinoblastoma. JCI Insight, Dec 2024. URL: https://doi.org/10.1172/jci.insight.188216, doi:10.1172/jci.insight.188216. This article has 2 citations and is from a domain leading peer-reviewed journal.

  22. (sun2024incidenceofsecond pages 1-2): Jinfeng Sun, Xiuli Gu, and Liangjun Wang. Incidence of second primary cancers in patients with retinoblastoma: a systematic review and meta-analysis. Frontiers in Oncology, Mar 2024. URL: https://doi.org/10.3389/fonc.2024.1372548, doi:10.3389/fonc.2024.1372548. This article has 8 citations.

  23. (sanidas2024patternsinthe pages 9-11): Ioannis Sanidas, Michael S. Lawrence, and Nicholas J. Dyson. Patterns in the tapestry of chromatin-bound rb. Trends in Cell Biology, 34:288-298, Apr 2024. URL: https://doi.org/10.1016/j.tcb.2023.07.012, doi:10.1016/j.tcb.2023.07.012. This article has 19 citations and is from a domain leading peer-reviewed journal.

Citations

  1. lai2024mechanismsunderlyingsusceptibility pages 12-15
  2. sizer2024selectiveoccupationby pages 1-2
  3. sanidas2024patternsinthe pages 4-6
  4. huang2024therapeuticstrategiesfor pages 2-4
  5. wang2024thesignificanceof pages 2-4
  6. park2023longitudinalmultiomicsstudy pages 14-15
  7. mai2024predictorsofresponse pages 1-2
  8. yu2024pharmacologicalmodulationof pages 1-2
  9. yu2024pharmacologicalmodulationof pages 5-5
  10. yousef2024mutationalanalysisof pages 1-2
  11. stacey2024prognosticimportanceof pages 1-2
  12. sun2024incidenceofsecond pages 1-2
  13. sanidas2024patternsinthe pages 3-4
  14. sanidas2024patternsinthe pages 6-8
  15. huang2024therapeuticstrategiesfor pages 10-12
  16. huang2024therapeuticstrategiesfor pages 9-10
  17. sanidas2024patternsinthe pages 9-11
  18. https://doi.org/10.1038/s41586-024-07554-2
  19. https://doi.org/10.1016/j.tcb.2023.07.012
  20. https://doi.org/10.3390/cancers16081558
  21. https://doi.org/10.3390/cancers16030481
  22. https://doi.org/10.1073/pnas.2304619121
  23. https://doi.org/10.1186/s13073-023-01201-7
  24. https://doi.org/10.1038/s41523-024-00699-3
  25. https://doi.org/10.3389/fmed.2024.1406215
  26. https://doi.org/10.1172/jci.insight.188216
  27. https://doi.org/10.3389/fonc.2024.1372548
  28. https://doi.org/10.1016/j.tcb.2023.07.012,
  29. https://doi.org/10.3389/fimmu.2024.1415972,
  30. https://doi.org/10.3390/cancers16081558,
  31. https://doi.org/10.3390/cancers16030481,
  32. https://doi.org/10.1038/s41586-024-07554-2,
  33. https://doi.org/10.1186/s13073-023-01201-7,
  34. https://doi.org/10.1038/s41523-024-00699-3,
  35. https://doi.org/10.1073/pnas.2304619121,
  36. https://doi.org/10.3389/fmed.2024.1406215,
  37. https://doi.org/10.1172/jci.insight.188216,
  38. https://doi.org/10.3389/fonc.2024.1372548,

📄 View Raw YAML

 
id: P06400
gene_symbol: RB1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  RB1 encodes the retinoblastoma-associated protein (pRb / p105-Rb / p110-RB1), the founding
  member of the pocket protein family and a nuclear, chromatin-bound tumor suppressor. Its core
  evolved activity is to enforce the G1 restriction point by binding activator E2F transcription
  factors (E2F1/2/3) through the RB_A/RB_B pocket domains, masking their transactivation domains
  and recruiting chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA
  methyltransferases, polycomb factors) to E2F-target promoters required for S-phase entry.
  Activity is switched off by sequential cyclin-CDK phosphorylation: Cyclin D-CDK4/6 and
  Cyclin E-CDK2 progressively phosphorylate ~16 Ser/Thr sites, with an early reversible
  intermediate phosphorylation at T373/S608 followed by cooperative C-terminal hyperphosphorylation
  (S780, S807/S811, T826) that fully releases E2F. Genome-wide ChIP studies show RB1 occupies
  thousands of loci across promoters, enhancers, and CTCF-bound sites, and the same scaffolding
  activity supports several non-canonical functions that are well documented but mechanistically
  downstream of the E2F-repression core: repression of RNA polymerase III transcription (via
  TFIIIB binding), genome maintenance (interactions with Ku70/Ku80/XRCC5/XRCC6 in cNHEJ and
  with BRG1 in HR-coupled programs), heterochromatin/SAHF formation in cellular senescence,
  and lineage-specific transcriptional cooperation with non-E2F partners (RUNX2, AR, CEBPD,
  PU.1). RB1 is the mutated locus in hereditary retinoblastoma and is recurrently lost in
  many adult tumors; its functional state is a clinically actionable biomarker for CDK4/6
  inhibitor response.
existing_annotations:
- term:
    id: GO:0031175
    label: neuron projection development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033. RB1 has documented roles in neuronal differentiation in vivo (e.g. murine Rb1 loss causes defects in retinal, cortical and CNS neuron development; the Rb/E2F axis regulates terminal differentiation in many neuronal lineages — deep research synthesis). However, neuron projection development is a tissue/cell-type-specific outcome of the broader Rb-E2F transcriptional repression program rather than a constitutive core RB1 function. The core RB1 function (Rb-E2F complex, G1/S transition repression, transcription coregulator activity, nucleoplasmic localization) is captured by other rows in this annotation set.'
    action: KEEP_AS_NON_CORE
    reason: 'Tissue/cell-type-specific neuronal differentiation context rather than a core RB1 function. Canonical RB1 activity (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental and IPI evidence elsewhere in this file (PMID:7923370; PMID:16360038 IPI on GO:0035189). Mechanical IBA-PANTHER batch (batch 6 of #347).'
- term:
    id: GO:0048667
    label: cell morphogenesis involved in neuron differentiation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033. As with GO:0031175 above, RB1 contributes to terminal neuronal differentiation in specific developmental contexts via the Rb-E2F transcriptional program, but cell morphogenesis involved in neuron differentiation is a downstream tissue-specific consequence rather than a core RB1 molecular/cellular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Tissue/cell-type-specific neuronal differentiation context rather than a core RB1 function. Canonical RB1 activity (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental and IPI evidence elsewhere in this file (PMID:7923370; PMID:16360038 IPI on GO:0035189). Mechanical IBA-PANTHER batch (batch 6 of #347).'
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for chromatin localization. Hypophosphorylated active RB1 is chromatin-bound at E2F target gene promoters and recruits chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) — this is a canonical, well-supported RB1 cellular localization (PMID:7923370; deep research synthesis). Chromatin binding is independently supported by direct experimental evidence elsewhere in this file.'
    action: ACCEPT
    reason: 'Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; PMID:17540172 IDA rows on heterochromatin/chromatin lock complex) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IBA-PANTHER batch (batch 6 of #347).'
- term:
    id: GO:0000977
    label: RNA polymerase II transcription regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for sequence-specific DNA binding at Pol II regulatory regions. RB1 itself does not contain a sequence-specific DNA-binding domain; its occupancy of E2F target gene promoters (E2F sites in regulatory regions) is mediated indirectly by binding the activator E2F1/2/3 transcription factors (which contain the sequence-specific winged-helix DNA-binding domain) via the RB_A/RB_B pocket. The sequence specificity is therefore contributed by E2F1/2/3, not by RB1. The closely related GO:0001012 (RNA polymerase II transcription regulatory region DNA binding) — which does not require the annotated protein to contribute the sequence-specific interface — is the appropriate term for RB1''s indirect, complex-mediated DNA occupancy.'
    action: MODIFY
    reason: 'Essence of the annotation (RB1 occupies Pol II regulatory regions via the Rb-E2F complex) is correct, but the "sequence-specific" qualifier of GO:0000977 does not apply to RB1: sequence specificity is contributed by E2F1/2/3 (winged-helix DNA-binding domain), while RB1 binds the E2F protein via the RB_A/RB_B pocket rather than DNA directly. Replace with GO:0001012 (RNA polymerase II transcription regulatory region DNA binding), which captures the regulatory-region occupancy without the sequence-specific binding claim. Mechanical IBA-PANTHER batch (batch 6 of #347); action adjusted in response to PR #490 review.'
    proposed_replacement_terms:
    - id: GO:0001012
      label: RNA polymerase II transcription regulatory region DNA binding
- term:
    id: GO:0035189
    label: Rb-E2F complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for the Rb-E2F complex. RB1 is the defining pocket-protein component of the Rb-E2F transcriptional repressor complex; the RB_A/RB_B pocket directly engages activator E2F1/2/3 transactivation domains and DP1/DP2 heterodimer partners to occupy E2F target gene promoters (PMID:7923370; deep research synthesis). Independently supported by IPI evidence (PMID:16360038) on this same GO:0035189 term elsewhere in this annotation set and by the parallel IEA Ensembl-Compara row ACCEPTed in PR #461.'
    action: ACCEPT
    reason: 'Canonical RB1 function — Rb-E2F complex is the namesake of the RB1 mechanism. Well supported by direct IPI evidence (PMID:16360038) on this exact term elsewhere in this file and by the parallel IEA row ACCEPTed in PR #461. Mechanical IBA-PANTHER batch (batch 6 of #347).'
- term:
    id: GO:2000134
    label: negative regulation of G1/S transition of mitotic cell cycle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: 'IBA annotation projected from the PANTHER PTHR13742 (RB/pocket-protein) family tree via GO_REF:0000033 for negative regulation of the G1/S transition. Hypophosphorylated RB1 sequesters activator E2F1/2/3 and prevents transcription of S-phase entry genes (CCNE1, CDC6, MCM2-7, etc.); CDK4/6-Cyclin D phosphorylation of RB1 inactivates this repression and licenses G1/S progression (PMID:7923370; deep research synthesis). This is one of the most canonical RB1 functions, central to its tumor-suppressor role.'
    action: ACCEPT
    reason: 'Canonical RB1 tumor-suppressor function — restraint of the G1/S transition via E2F sequestration is one of the best-characterized RB1 activities. Well supported by direct experimental and Reactome TAS evidence elsewhere in this file (PMID:19149898 TAS rows on G1/S regulation; ACCEPTed in earlier batches). Mechanical IBA-PANTHER batch (batch 6 of #347).'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'IEA annotation propagated via UniProt-keyword/InterPro2GO (GO_REF:0000120) for nuclear localization. RB1 is a canonical nuclear protein; hypophosphorylated active RB1 occupies E2F-target gene promoters in the nucleoplasm and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis). Nuclear localization is also independently supported by IDA (PMID:1531329, PMID:20940255) and by 17 Reactome TAS rows on GO:0005654 nucleoplasm already ACCEPTed in PR #444.'
    action: ACCEPT
    reason: 'Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'IEA annotation propagated via UniProt-keyword/InterPro2GO (GO_REF:0000120) for cytoplasmic localization. RB1 is canonically a nuclear protein (active hypophosphorylated RB1 occupies E2F-target promoters in the nucleoplasm), but cytoplasmic localization is a real conditional secondary state. UniProt P06400 CC SUBCELLULAR LOCATION records cytoplasmic localization "when hyperphosphorylated (By similarity)" (projected from mouse Rb1 P13405) and additionally notes that interaction with PKP3 (Plakophilin 3) may sequester RB1 to the cytoplasm (By similarity, from P13405). PMID:20940255 (Pickard et al. 2010) independently shows RB1 mislocalizes to the cytoplasm when not PCAF-acetylated during keratinocyte differentiation. None of these cytoplasmic contexts represent the canonical Rb-E2F transcriptional corepressor function captured by core_functions[0].'
    action: KEEP_AS_NON_CORE
    reason: 'Cytoplasmic localization is a real but non-core secondary state — represents inactive/sequestered or apoptotic-context RB1, downstream of the defining nuclear Rb-E2F transcriptional corepressor activity already ACCEPTed (GO:0005634 nucleus IEA in batch 5; 17 Reactome TAS GO:0005654 nucleoplasm rows ACCEPTed in PR #444; PMID:20940255 EXP nuclear localization). Same precedent as the GO:0005819 spindle KEEP_AS_NON_CORE row in batch 15 (#551) — IEA localization counterpart to a non-core RB1 functional context.'
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: 'IEA annotation propagated via InterPro2GO (GO_REF:0000002) for regulation of transcription by RNA polymerase II. RB1 is a chromatin-bound corepressor of Pol II transcription, primarily through binding and inhibition of activator E2F1/2/3 transcription factors at the RB_A/RB_B pocket and recruitment of chromatin-modifying complexes (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis). Pol II transcriptional regulation is also captured by GO:0000122 TAS (PMID:19149898) elsewhere in this file.'
    action: ACCEPT
    reason: 'Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).'
- term:
    id: GO:0032502
    label: developmental process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: 'IEA annotation propagated via GO_REF:0000117 (electronic, ARBA/InterPro2GO-type)
      for the high-level grouping term developmental process. RB1 is a pleiotropic
      tumor suppressor whose non-canonical biology genuinely extends to promotion of
      differentiation across multiple lineages (myocytes, adipocytes, erythroid and
      neuronal precursors) and to senescence and lineage-fidelity maintenance (deep
      research synthesis: sanidas2024patternsinthe; huang2024therapeuticstrategiesfor;
      corroborated by PMID:9448006 discussion noting nonphosphorylated pRB promotes
      differentiation of myocytes, adipocytes, erythroid and neuronal cells). However,
      developmental process is an extremely broad grouping term and these developmental
      roles are downstream contexts of, not equivalent to, the defining Rb-E2F G1/S
      transcriptional corepressor activity captured by core_functions[0].'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s developmental roles are real and literature-supported but represent
      pleiotropic non-core contexts downstream of the defining Rb-E2F cell-cycle corepressor
      function (already ACCEPTed: GO:0051726 regulation of cell cycle, GO:0006357 regulation
      of transcription by Pol II, the GO:0045892 IDA rows, and the 17 Reactome nucleoplasm
      TAS rows). Same KEEP_AS_NON_CORE precedent as the GO:0005737 cytoplasm and GO:0005819
      spindle (batch 15, #551) rows — a real but non-core IEA aspect retained on record
      rather than removed. The term is too high-level to be core; it is not wrong.'
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: 'IEA annotation propagated via UniProt-keyword/InterPro2GO (GO_REF:0000120) for regulation of cell cycle. RB1 is the prototypical pocket-protein G1/S-checkpoint regulator; hypophosphorylated RB1 represses E2F-driven S-phase entry and is two-step inactivated by Cyclin D-CDK4/6 then Cyclin E-CDK2 phosphorylation (PMID:7923370; deep research synthesis). Cell-cycle regulation is also captured by GO:2000134 TAS (PMID:19149898) and multiple IDA/IMP rows elsewhere in this file.'
    action: ACCEPT
    reason: 'Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10779361
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10944455
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11268000
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12434308
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12502741
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12598654
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12743606
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12813456
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:1331501
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14555653
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14645241
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15084261
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16061792
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16249186
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16286473
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16360038
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16374512
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16510145
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16616919
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16763564
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16766265
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17045206
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17274640
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17292836
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17349581
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17380128
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17620057
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18391203
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:1870208
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19017275
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19249677
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19513100
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19651603
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20088881
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20195357
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20871633
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21119616
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21139044
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:2138977
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:2153075
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:2162480
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:2189724
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21952639
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22157815
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22301153
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22366686
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22615382
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22773103
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22810586
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22898364
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23472054
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23602568
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23752268
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23783631
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23859194
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24823443
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25609649
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25814554
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29521627
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29997244
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32707033
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591612
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591642
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35140242
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39938803
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7592647
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7664264
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7791904
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7890747
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7923370
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8756624
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9067421
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9468139
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9468140
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9608663
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9697699
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9881977
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16360038
  review:
    summary: 'Rubin et al. 2005 (PMID:16360038, Cell) is the crystal structure of
      the Rb C-terminal domain (RbC) bound to the E2F1-DP1 heterodimer. It characterizes
      a high-affinity heterotypic interaction in which RbC contacts the marked-box
      domains of E2F1 and DP1, plus a phosphorylation-induced intramolecular RbC-pocket
      contact within a single RB1 molecule. It does not demonstrate RB1 homodimerization
      or RB1-RB1 self-association, and RB1 is not characterized as a homodimer in its
      core E2F-repression / chromatin-scaffolding biology. GO:0042802 identical protein
      binding implies an RB1-RB1 interaction that this paper does not support. The
      informative interactions from this structure are already captured by the batch-17
      ACCEPT rows GO:0035189 (Rb-E2F complex) and GO:0060090 (molecular adaptor activity).'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'The cited Rubin 2005 structure characterizes heterotypic RbC-E2F1-DP1
      binding, not RB1 self-association; identical protein binding is an unsupported,
      uninformative generic binding term for this evidence. Conservative demotion consistent
      with the GO:0005515 precedent in this same review and the batch-17 handling of
      PMID:16360038. A second independent GO:0042802 row (PMID:8288605) remains PENDING
      and is deferred to a later batch.'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:8288605
  review:
    summary: 'IPI annotation for identical protein binding sourced from Hensey et al. 1994 (PMID:8288605). This study expressed and purified recombinant full-length human p110RB and an N-terminally truncated p56RB, and used non-denaturing PAGE, electron microscopy and yeast two-hybrid analysis to show that full-length RB1 self-associates into oligomeric/higher-order structures via interactions between its amino- and carboxy-terminal domains, a property absent from the N-terminally truncated form. This is genuine, specific evidence for RB1 homo-oligomerization (identical protein binding), distinct from the heterotypic RbC-E2F1-DP1 contacts cited for the other GO:0042802 row (PMID:16360038) that was demoted because that source did not characterize self-association.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1 self-oligomerization is a real, specifically-evidenced biochemical property (yeast two-hybrid + native PAGE + EM in PMID:8288605), so the term is correctly supported here and is informative rather than generic protein binding. However it is a secondary structural property, not the defining E2F-pocket corepressor / chromatin-scaffold activity captured by core_functions[0] (GO:0003714); kept on record at non-core priority. This resolves the GO:0042802 (PMID:8288605) row explicitly deferred by the batch-17 handling of the PMID:16360038 counterpart. Mechanical binding-partner-MF batch (batch 22 of #347).'
- term:
    id: GO:0002062
    label: chondrocyte differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Tissue-specific differentiation phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): Rb1 is required for chondrocyte differentiation and endochondral ossification in conditional-knockout mouse skeletal models, but this is a downstream lineage-specific consequence of RB1''s core E2F-repression / chromatin-scaffolding activity (e.g. partnering with RUNX2 in cartilage/bone progenitors) rather than a primary RB1 molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Tissue-specific developmental phenotype projected from mouse Rb1 ortholog: Rb1-null mouse hearts exhibit cardiac valve defects, but this is a downstream developmental consequence of Rb1''s core role in E2F-mediated proliferation/differentiation control in cardiac neural crest and valvular interstitial cells, not a primary RB1 molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0005667
    label: transcription regulator complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for transcription regulator complex. RB1 is the defining component of the Rb-E2F transcriptional repressor complex and broadly participates in chromatin-bound transcription regulator assemblies with HDAC1, SUV39H1, BRG1/SMARCA4, and lineage-specific TFs (PMID:7923370; deep research synthesis). Independently supported by the more specific GO:0035189 Rb-E2F complex IPI rows in this file.'
    action: ACCEPT
    reason: 'Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).'
- term:
    id: GO:0005819
    label: spindle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for spindle localization. RB1 has a documented but non-core mitotic-fidelity role at the centromere/condensin II axis (CAP-D3 mislocalization, merotelic attachment, lagging chromosomes) shown by Manning et al. 2010 PMID:20551165 — this is the same mitotic-fidelity biology that motivates spindle-adjacent localization, but it is downstream of, and tangential to, RB1''s defining function as the Rb-E2F transcriptional corepressor that enforces the G1/S restriction point.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1''s primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Spindle IEA projected from mouse Rb1 ortholog (GO_REF:0000107) is the localization counterpart to the PMID:20551165 mitotic-fidelity IMP cluster already KEEP_AS_NON_CORE in batch 11 of #347.'
- term:
    id: GO:0006915
    label: apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Downstream phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): Rb1 loss sensitises cells to apoptosis through deregulated E2F1-driven proapoptotic gene programs (e.g. p73, BIM, APAF1) and altered Bcl-2-family balance, but apoptotic engagement is a context-dependent consequence of RB1''s core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 molecular function. Consistent with the existing KEEP_AS_NON_CORE treatment of GO:2001234 negative regulation of apoptotic signaling pathway (ISS PMID:24027266) elsewhere in this file.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0007283
    label: spermatogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Tissue-specific developmental phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): germ-cell-conditional Rb1 deletion in the mouse compromises spermatogonial / Sertoli-cell programs and male fertility, but spermatogenesis is a downstream lineage-specific consequence of RB1''s core E2F-repression / chromatin-scaffolding role in proliferating progenitors rather than a primary RB1 molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for enzyme binding. GO:0019899 is an uninformative generic MF parent term that captures the broad class of RB1''s enzymatic-partner interactions without naming what RB1 actually does mechanistically. RB1''s informative enzyme-binding biology is already captured at higher specificity by the chromatin-modifying enzyme interactions ACCEPTed in this file (HDAC1, SUV39H1, BRG1/SMARCA4 corepressor recruitment via the RB_A/RB_B pocket; PMID:7923370 RB-BRG1 cooperation; deep research synthesis) and by the GO:0001047 / GO:0003682 chromatin-binding rows. Per CLAUDE.md curation guidelines, generic adapter/binding parent terms should be demoted in favor of more specific MF annotations.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Generic enzyme binding is uninformative for RB1''s well-characterized adapter/scaffolding biology with chromatin-modifying enzymes (HDAC1, SUV39H1, BRG1/SMARCA4) and cell-cycle kinases (CDK4/CDK6 phosphorylation of RB1). Same precedent as the uniform demotion of generic GO:0005515 protein binding IPI rows in this file (50+ rows ACCEPTed as MARK_AS_OVER_ANNOTATED per BAG3 #313 / KRAS #349 / BCAP31 PR #317 / RB1 PR #430 precedent).'
- term:
    id: GO:0030308
    label: negative regulation of cell growth
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for negative regulation of cell growth. RB1 is the prototypical pocket-protein antiproliferative tumor suppressor: hypophosphorylated RB1 binds activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, masks their transactivation domains, recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) and durably represses S-phase gene transcription, thereby restricting net cellular growth and proliferation (PMID:7923370; deep research synthesis). Already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9 and the GO:0051726 regulation of cell cycle IEA row ACCEPTed in batch 5.'
    action: ACCEPT
    reason: 'Canonical RB1 antiproliferative function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 14 of #347).'
- term:
    id: GO:0032869
    label: cellular response to insulin stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Tissue-specific metabolic phenotype projected from mouse Rb1 ortholog via Ensembl Compara (IEA GO_REF:0000107): Rb1 modulates insulin sensitivity in adipocytes and beta cells through E2F-mediated control of metabolic / differentiation gene programs (paralleling the existing GO:0120163 cold-induced thermogenesis ISS row at line 1296), but insulin-stimulus response is a context-dependent metabolic consequence of RB1''s core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0035189
    label: Rb-E2F complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for Rb-E2F complex. RB1 is the defining pocket-protein component of the Rb-E2F transcriptional repressor complex; the RB_A/RB_B pocket directly engages activator E2F1/2/3 transactivation domains and DP heterodimer partners to occupy E2F target gene promoters (PMID:7923370; deep research synthesis). Independently supported by IPI evidence (PMID:16360038) on this exact term elsewhere in this file.'
    action: ACCEPT
    reason: 'Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).'
- term:
    id: GO:0045786
    label: negative regulation of cell cycle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for negative regulation of cell cycle. Negative regulation of cell-cycle progression is the defining RB1 tumor-suppressor activity: hypophosphorylated RB1 sequesters activator E2Fs and represses S-phase genes at the G1 restriction point until it is sequentially inactivated by Cyclin D-CDK4/6 and Cyclin E-CDK2 phosphorylation (PMID:7923370; deep research synthesis). Already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9 and the GO:0051726 regulation of cell cycle IEA row ACCEPTed in batch 5.'
    action: ACCEPT
    reason: 'Canonical RB1 cell-cycle-restriction function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 14 of #347).'
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 loss can increase tissue inflammation as part of the senescence-associated secretory phenotype (SASP) and altered chromatin programs, but inflammatory regulation is a contextual consequence of RB1''s core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for RNA polymerase II-specific DNA-binding transcription factor binding. RB1 directly binds the E2F1/2/3 activator transcription factors (sequence-specific Pol II TFs) via its RB_A/RB_B pocket; this is the canonical RB1 molecular function (PMID:7923370; deep research synthesis). Independently supported by IPI evidence on the related Rb-E2F complex (GO:0035189) and by core_functions[0] in this file.'
    action: ACCEPT
    reason: 'Canonical RB1 function/localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical IEA-canonical batch (batch 5 of #347).'
- term:
    id: GO:0120163
    label: negative regulation of cold-induced thermogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Tissue-specific phenotype projected from mouse Rb1: Rb1 represses brown-adipocyte / thermogenic gene programs (Ucp1) in white adipose tissue (PMID:19417128), but cold-induced thermogenesis is a downstream metabolic consequence of RB1''s role in adipocyte differentiation/transcription control rather than a core RB1 function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'IEA annotation projected from mouse Rb1 via Ensembl Compara (GO_REF:0000107) for DNA-binding transcription factor binding. RB1 binds multiple sequence-specific DNA-binding transcription factors — most prominently activator E2F1/2/3 via the RB_A/RB_B pocket, and lineage-specific TFs (RUNX2, AR, CEBPD, PU.1) in differentiation contexts (PMID:7923370; deep research synthesis). Same canonical function captured more specifically by GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding) which is also ACCEPTed in this file, and all of RB1''s characterised TF-binding partners (E2F1/2/3, RUNX2, AR, CEBPD, PU.1) are Pol II-specific TFs, so the parent adds no additional biological information beyond what the child captures.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Parent term of GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), which is ACCEPTed in this same batch and captures the full scope of RB1''s TF-binding biology — every characterised RB1 partner (E2F1/2/3, RUNX2, AR, CEBPD, PU.1) is a Pol II-specific TF, so the more general GO:0140297 is not entirely wrong but represents an over-annotation per the schema definition.'
- term:
    id: GO:1903055
    label: positive regulation of extracellular matrix organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 modulates ECM organization through transcriptional control of stromal/fibroblast programs, but ECM organization is a contextual consequence of RB1''s core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:1903944
    label: negative regulation of hepatocyte apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Tissue-specific phenotype projected from mouse Rb1 ortholog: Rb1 modulates hepatocyte apoptosis sensitivity in liver-specific contexts, but this is a downstream tissue-level consequence of RB1''s core E2F / cell-cycle / chromatin role rather than a primary molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:1904028
    label: positive regulation of collagen fibril organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 affects collagen-fibril organization via transcriptional regulation of stromal programs, but collagen-fibril organization is a contextual consequence of RB1''s core role in cell-cycle / differentiation control rather than a primary molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:1904761
    label: negative regulation of myofibroblast differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Tissue-specific phenotype projected from mouse Rb1 ortholog: Rb1 restricts myofibroblast differentiation programs in fibrotic contexts, but this is a downstream cell-fate consequence of RB1''s core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:2001234
    label: negative regulation of apoptotic signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: 'Downstream phenotype projected from mouse Rb1 ortholog: Rb1 affects apoptotic signaling sensitivity through E2F-target regulation (e.g. via BCL-2 family genes and cell-cycle/apoptosis crosstalk), but apoptotic-pathway regulation is a context-dependent consequence of RB1''s core E2F-repression / chromatin-scaffolding role rather than a primary RB1 function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17540172
  review:
    summary: 'IDA annotation for nuclear localization sourced from the chromatin lock complex paper (Trojer et al. 2007 Cell, PMID:17540172). RB1 was co-purified with L3MBTL1, core histones, histone H1b, and HP1gamma as a chromatin-bound nuclear complex that compacts facultative heterochromatin. Nuclear localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444) and by IEA propagations ACCEPTed in PR #461.'
    action: ACCEPT
    reason: 'Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444) and by the L3MBTL1 chromatin-lock complex co-purification reported in PMID:17540172. Mechanical PMID:17540172-cluster batch (batch 7 of #347).'
- term:
    id: GO:0031507
    label: heterochromatin formation
  evidence_type: IDA
  original_reference_id: PMID:17540172
  review:
    summary: 'IDA annotation from the L3MBTL1 chromatin lock complex paper (Trojer et al. 2007 Cell, PMID:17540172). The L3MBTL1 MBT domains, in a complex with RB1, core histones, histone H1b, and HP1gamma, compact nucleosomal arrays dependent on mono- and dimethylation of histone H4 lysine 20 and histone H1b lysine 26 — the defining biochemistry of facultative heterochromatin formation. RB1 participates in this chromatin-compaction activity as a stoichiometric complex member.'
    action: ACCEPT
    reason: 'Canonical RB1 function, directly supported by IDA evidence in PMID:17540172 showing RB1 in the L3MBTL1 chromatin lock complex that compacts nucleosomal arrays into facultative heterochromatin. Consistent with RB1''s broader role in chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) captured in core_functions[0]. Mechanical PMID:17540172-cluster batch (batch 7 of #347).'
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:17540172
  review:
    summary: 'IMP annotation from the L3MBTL1 chromatin lock complex paper (Trojer et al. 2007 Cell, PMID:17540172). L3MBTL1, in a complex with RB1, was shown to negatively regulate the expression of a subset of genes regulated by E2F — directly linking the chromatin-lock biochemistry to repression of RB-E2F target genes. This is a canonical RB1 transcriptional repressor function delivered via chromatin compaction rather than only via E2F transactivation-domain masking.'
    action: ACCEPT
    reason: 'Canonical RB1 function, well supported by IMP evidence in PMID:17540172 (L3MBTL1+RB1 chromatin lock represses a subset of E2F target genes) and consistent with the broader RB-E2F repressor mechanism captured in core_functions[0]. Mechanical PMID:17540172-cluster batch (batch 7 of #347).'
- term:
    id: GO:0061793
    label: chromatin lock complex
  evidence_type: IPI
  original_reference_id: PMID:17540172
  review:
    summary: 'IPI annotation from the namesake paper (Trojer et al. 2007 Cell, PMID:17540172) — RB1 co-purifies with L3MBTL1, core histones, histone H1b, and HP1gamma as the chromatin lock complex. GO:0061793 chromatin lock complex was defined for this exact biochemistry. RB1 is a stoichiometric component of this complex and contributes the E2F-target-gene specificity that links the L3MBTL1 H4K20me1/2-reading chromatin-compaction activity to RB1-controlled promoter sets.'
    action: ACCEPT
    reason: 'RB1 is a defining stoichiometric component of the chromatin lock complex per the namesake paper (PMID:17540172, IPI partner = L3MBTL1; cross-supports the same paper''s IDA/IMP entries for GO:0031507 heterochromatin formation and GO:0045892 negative regulation of DNA-templated transcription already in this batch). Mechanical PMID:17540172-cluster batch (batch 7 of #347).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: 'IDA annotation for nucleoplasmic localization sourced from the Human Protein Atlas immunofluorescence curation (GO_REF:0000052). RB1 is a canonical nuclear/nucleoplasmic protein; hypophosphorylated active RB1 occupies E2F-target gene promoters in the nucleoplasm and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis). Nucleoplasmic localization is also independently supported by 17 Reactome TAS rows on GO:0005654 already ACCEPTed in PR #444 and by IEA propagations ACCEPTed in PR #461.'
    action: ACCEPT
    reason: 'Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444) and by HPA immunofluorescence curation (GO_REF:0000052). Mechanical canonical-nuclear-localization batch (batch 10 of #347).'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:1531329
  review:
    summary: 'IDA annotation for nuclear localization sourced from the RB-E2F interaction paper (Hiebert et al. 1992 Genes Dev, PMID:1531329). The paper demonstrates that RB1 interacts with E2F in a complex that inhibits E2F transcriptional activity, with the in vivo biochemistry performed on nuclear extracts. Nuclear localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444), by IEA propagations ACCEPTed in PR #461, and by the IDA nucleoplasm row from PMID:17540172 ACCEPTed in PR #499.'
    action: ACCEPT
    reason: 'Canonical RB1 localization, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444). The Hiebert et al. 1992 paper is the canonical RB-E2F interaction paper and directly supports nuclear localization of RB1. Mechanical canonical-nuclear-localization batch (batch 10 of #347).'
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:1531329
  review:
    summary: 'IDA annotation from Hiebert et al. 1992 (PMID:1531329, "The interaction
      of RB with E2F coincides with an inhibition of the transcriptional activity
      of E2F"), a canonical RB-E2F repression paper. Transfection assays of the adenovirus
      E2 promoter show that "formation of the complex containing pRB and E2F coincides
      with an inhibition of E2F-dependent transcriptional activity" and that "a mutant
      pRB protein that does not associate with E2F does not inhibit transcription."
      This directly demonstrates that RB1 *negatively* (not merely "regulates") regulates
      DNA-templated transcription. The generic parent GO:0006355 is too broad for
      this directional finding; the specific child GO:0045892 (negative regulation
      of DNA-templated transcription) is exactly what is shown, is already captured
      in core_functions[0].directly_involved_in, and is concordantly supported by
      IDA/TAS rows elsewhere in this file (PMID:12065415, PMID:10783144, PMID:19223331,
      PMID:19149898).'
    action: MODIFY
    reason: 'Essence of the annotation (RB1 represses transcription via the Rb-E2F
      complex) is correct and canonical, but GO:0006355 is too general for the directional
      repressor activity that PMID:1531329 directly demonstrates. Replace with GO:0045892
      (negative regulation of DNA-templated transcription), the specific term already
      present in core_functions[0]. Mechanical transcription-regulation batch (batch
      20 of #347).'
    proposed_replacement_terms:
    - id: GO:0045892
      label: negative regulation of DNA-templated transcription
- term:
    id: GO:0035189
    label: Rb-E2F complex
  evidence_type: IPI
  original_reference_id: PMID:16360038
  review:
    summary: 'IPI annotation for the Rb-E2F complex sourced from Rubin et al. 2005 (PMID:16360038, Cell), the landmark crystal structure of the Rb C-terminal domain (RbC) bound to the E2F1-DP1 heterodimer. The paper demonstrates a high-affinity RbC-E2F-DP interaction shared by all Rb and E2F family members and resolves an intertwined heterodimer in which the marked box domains of both E2F1 and DP1 contact RbC. This is direct structural evidence for the namesake Rb-E2F complex — the defining RB1 assembly already captured by core_functions[0] (in_complex: GO:0035189) and independently supported by the IBA GO:0035189 row ACCEPTed in batch 6 (which cites this same PMID:16360038 as its IPI anchor) and the parallel IEA Ensembl-Compara row ACCEPTed in PR #461.'
    action: ACCEPT
    reason: 'Canonical RB1 function — the Rb-E2F complex is the namesake of the RB1 mechanism and is directly demonstrated at atomic resolution by PMID:16360038 (Rubin et al. 2005 RbC-E2F1-DP1 crystal structure). Reinforces core_functions[0] (in_complex: GO:0035189) and is consistent with the IBA GO:0035189 row already ACCEPTed in batch 6 and the IEA row ACCEPTed in PR #461. PMID:16360038 (Rubin et al. 2005) canonical RB-E2F structural batch (batch 17 of #347).'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:20940255
  review:
    summary: 'EXP annotation for nuclear localization sourced from Pickard et al. 2010 (PMID:20940255), "Acetylation of Rb by PCAF is required for nuclear localization and keratinocyte differentiation." The paper directly characterizes RB1 nuclear localization and shows that PCAF-mediated acetylation of Rb is required for its retention in the nucleus during keratinocyte differentiation. Nuclear localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444) and by IEA propagations ACCEPTed in PR #461.'
    action: ACCEPT
    reason: 'Canonical RB1 localization, directly characterized by the cited paper (PMID:20940255) — RB1 nuclear localization is the explicit subject of the Pickard et al. 2010 study. Also independently supported by 17 Reactome TAS nucleoplasm rows ACCEPTed in PR #444 and by canonical IEA propagations. Mechanical canonical-nuclear-localization batch (batch 10 of #347).'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'ISS annotation projected from mouse Rb1 (UniProtKB:P13405) via GO_REF:0000024 for cytoplasmic localization. Same biology as the parallel IEA GO_REF:0000120 cytoplasm row in this file: cytoplasmic localization is a real but conditional secondary state. UniProt P06400 CC SUBCELLULAR LOCATION records cytoplasmic localization "when hyperphosphorylated (By similarity)" plus PKP3 (Plakophilin 3) interaction-mediated sequestration (both By similarity from P13405); PMID:20940255 independently shows RB1 mislocalizes to the cytoplasm when not PCAF-acetylated during keratinocyte differentiation. Not the canonical Rb-E2F nuclear corepressor function captured by core_functions[0].'
    action: KEEP_AS_NON_CORE
    reason: 'Cytoplasmic localization is a real but non-core secondary state — represents inactive/sequestered or apoptotic-context RB1, downstream of the defining nuclear Rb-E2F transcriptional corepressor activity already ACCEPTed (GO:0005634 nucleus IEA in batch 5; 17 Reactome TAS GO:0005654 nucleoplasm rows ACCEPTed in PR #444; PMID:20940255 EXP nuclear localization). Same precedent as the GO:0005819 spindle KEEP_AS_NON_CORE row in batch 15 (#551). Resolves both PENDING cytoplasm rows (IEA + ISS) in a single batch since they describe identical biology from parallel propagation routes.'
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews hypophosphorylated pRb as a Pol II transcriptional corepressor that silences E2F-target S-phase genes via the RB-E2F repressor complex (and recruits chromatin-modifying partners HDAC1, BRM, BRG1/SMARCA4). Negative regulation of Pol II transcription is a canonical core RB1 activity; already ACCEPTed elsewhere in this file via IEA (GO_REF:0000107) and supported by IDA evidence on PMID:7923370 and PMID:1531329.'
    action: ACCEPT
    reason: 'Negative regulation of Pol II transcription is one of the best-characterized RB1 activities and is consistent with the existing core_functions[0] block (E2F repression at S-phase promoters). PMID:19149898 explicitly describes pRb as forming "active pRb-E2F transcriptional repressor complexes that silence genes required for S-phase entry." Mechanical TAS batch (batch 9 of #347) — all 8 PMID:19149898 TAS rows describe canonical RB1 repressor/cell-cycle functions and are uniformly ACCEPTed in this batch.'
- term:
    id: GO:2000134
    label: negative regulation of G1/S transition of mitotic cell cycle
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews the prototypical RB1 function at the G1/S restriction point — hypophosphorylated pRb sequesters E2F1/2/3 and prevents S-phase entry until inactivated by Cyclin D-CDK4/6 and Cyclin E-CDK2 phosphorylation. Negative regulation of G1/S is a canonical core RB1 activity, already captured elsewhere in this file via IBA (PR #490, GO_REF:0000033) and IEA propagation.'
    action: ACCEPT
    reason: 'Negative regulation of the G1/S transition is the defining RB1 tumor-suppressor activity, central to the existing core_functions[0] block. PMID:19149898 directly describes the CDK4/6/Cyclin D - pRb - E2F switch at the G1/S restriction point. Mechanical TAS batch (batch 9 of #347).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188386
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188390
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-69227
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0051276
    label: chromosome organization
  evidence_type: IMP
  original_reference_id: PMID:20551165
  review:
    summary: 'IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB depletion compromises centromeric localization of CAP-D3/condensin II and chromosome cohesion, leading to merotelic attachment and chromosome missegregation. Real RB1 biology — RB1 loss undermines mitotic fidelity via condensin II / centromere effects — but this is a non-cell-cycle-arrest mitotic phenotype that is downstream of, and tangential to, RB1''s defining function as the Rb-E2F transcriptional corepressor that enforces the G1/S restriction point. The Manning study explicitly frames this as separate from RB1''s "best-known regulation of the G1/S-phase transition."'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1''s primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.'
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: EXP
  original_reference_id: PMID:16360038
  review:
    summary: 'EXP annotation for molecular adaptor activity sourced from Rubin et al. 2005 (PMID:16360038, Cell). The crystal structure of RbC bound to E2F1-DP1 shows RbC forming an intertwined heterodimer that simultaneously contacts the marked box domains of both E2F1 and DP1, while the Rb pocket independently engages the E2F transactivation domain. RB1 thereby acts as a molecular adaptor/scaffold that bridges the activator E2F-DP heterodimer to the pocket and, in the cellular context, to recruited chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) — the bridging architecture underpinning core_functions[0] (masking E2F transactivation domains and recruiting chromatin corepressors). Per CLAUDE.md curation guidelines, this informative adaptor MF term is preferred over the generic GO:0005515 protein binding rows uniformly demoted elsewhere in this file.'
    action: ACCEPT
    reason: 'Canonical RB1 scaffolding/adaptor molecular function, demonstrated by direct experimental (EXP) structural evidence in PMID:16360038 (Rubin et al. 2005): RbC simultaneously bridges the E2F1 and DP1 marked box domains, the structural basis for RB1 tethering activator E2F-DP heterodimers to the pocket and to recruited chromatin corepressors. Informative MF term preferred over generic protein binding per CLAUDE.md, and consistent with the bridging mechanism described in core_functions[0]. PMID:16360038 (Rubin et al. 2005) canonical RB-E2F structural batch (batch 17 of #347).'
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:19223331
  review:
    summary: 'IPI annotation for DNA-binding transcription factor binding citing Stros et al. 2009 (PMID:19223331). In this study, GST pull-down and co-immunoprecipitation demonstrate a direct physical pRb-HMGB1 interaction, and ectopic pRb suppresses HMGB1/HMGB2-driven transactivation of the topo IIalpha (TOP2A) promoter by modulating NF-Y occupancy. RB1 binding DNA-binding transcription factors is a genuine RB1 molecular activity (canonically activator E2F1/2/3 via the RB_A/RB_B pocket, plus lineage-specific TFs), but the same biology is captured more specifically by GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), already ACCEPTed in this file, since every characterised RB1 TF partner (E2F1/2/3, RUNX2, AR, CEBPD, PU.1; and the Pol II-context HMGB1/NF-Y axis here) is Pol II-specific.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Consistent with the established in-file decision on the GO:0140297 IEA row (GO_REF:0000107): GO:0140297 is the over-general parent of GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), which is ACCEPTed and captures the full scope of RB1''s TF-binding biology. The parent adds no biological information beyond the ACCEPTed child, so the term is not wrong but represents an over-annotation. The PMID:19223331 pRb-HMGB1 interaction is a Pol II transcription-context interaction already covered by the child term. Mechanical binding-partner-MF batch (batch 22 of #347).'
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes hypophosphorylated pRb as a transcriptional corepressor that represses E2F-target promoters via chromatin remodeling — including direct interactions with HDAC1, BRM, and the SWI/SNF catalytic subunit BRG1/SMARCA4. Transcription corepressor activity is a canonical RB1 MF activity already supported by IDA evidence elsewhere in this file.'
    action: ACCEPT
    reason: 'Transcription corepressor activity is one of the defining biochemical activities of RB1 at E2F-target promoters and is consistent with the existing core_functions[0] block. PMID:19149898 explicitly frames pRb as forming "transcriptional repressor complexes that silence genes required for S-phase entry." Mechanical TAS batch (batch 9 of #347).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9659782
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-113503
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-187948
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9687377
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9851127
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: TAS
  original_reference_id: PMID:3657987
  review:
    summary: 'TAS annotation for nuclear localization sourced from Lee et al. 1987 Nature (PMID:3657987), the foundational paper that identified the retinoblastoma gene product as a nuclear phosphoprotein. The paper explicitly states that "biochemical fractionation and immunofluorescence studies demonstrate that the majority of the protein is located within the nucleus." This is the original characterization of RB1 as a nuclear protein and is independently corroborated by 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444), IDA evidence (PMID:17540172 in PR #499, PMID:1531329, PMID:20940255 in this batch), and canonical IEA propagations ACCEPTed in PR #461.'
    action: ACCEPT
    reason: 'Canonical RB1 localization established in the foundational Lee et al. 1987 Nature paper (PMID:3657987), which directly demonstrates nuclear localization by both biochemical fractionation and immunofluorescence. Nuclear localization is one of the defining features of RB1 from the moment the gene was cloned. Mechanical canonical-nuclear-localization batch (batch 10 of #347).'
- term:
    id: GO:0030308
    label: negative regulation of cell growth
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'ISS annotation projected via UniProt/InterPro template (GO_REF:0000024) for negative regulation of cell growth, based on conservation of the RB pocket domain. RB1 is the prototypical pocket-protein antiproliferative tumor suppressor: hypophosphorylated RB1 binds activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket and represses S-phase gene transcription, restricting net cellular growth and proliferation (PMID:7923370; deep research synthesis). Already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9.'
    action: ACCEPT
    reason: 'Canonical RB1 antiproliferative function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical ISS-canonical batch (batch 14 of #347).'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9660615
  review:
    summary: TAS annotation for cytosolic localization sourced from a Reactome disease event ('Defective RB1 does not translocate to the nucleus') describing loss-of-function RB1 nonsense/frameshift/NLS-deletion mutants (e.g. RB1 R830_G887 / delEx24-25) that lack the bipartite C-terminal NLS (residues 860-876) and are retained in the cytosol (PMID:8413247 Zacksenhaus et al. 1993; PMID:9326330 Bremner et al. 1997). Wild-type RB1 is a nuclear chromatin-bound corepressor; cytosolic retention is restricted to NLS-loss tumor mutants and is therefore a pathological mislocalization rather than a constitutive cellular compartment for the wild-type protein.
    action: KEEP_AS_NON_CORE
    reason: 'Real biology in a disease/mutant context (NLS-loss RB1 cancer mutants retained in the cytosol) but not a core wild-type RB1 localization. RB1''s core compartment is the nucleus / nucleoplasm, where it carries out E2F repression and chromatin scaffolding (already ACCEPTed via the 17 R-HSA nucleoplasm TAS rows). Keeping on record at non-core priority is consistent with the analogous treatment of disease/ortholog-projected rows already in this file (e.g. PMID:24027266 GO:2001234 apoptosis row at line 1287 and PMID:19417128 GO:0120163 thermogenesis row at line 1296).'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9659820
  review:
    summary: TAS annotation for cytosolic localization sourced from the Reactome event 'RB1 translocates to the nucleus', which describes the bipartite C-terminal NLS-dependent (residues 860-876) translocation of RB1 from the cytosol to the nucleus (PMID:8413247 Zacksenhaus et al. 1993). In the absence of the NLS only a small portion of RB1 reaches the nucleus while a large portion is retained in the cytosol. Cytosolic localization is therefore a transient pre-import state and an NLS-loss-mutant pathological state, not the steady-state compartment for the active wild-type protein.
    action: KEEP_AS_NON_CORE
    reason: 'Real biology in a disease/mutant context (NLS-loss RB1 cancer mutants retained in the cytosol) but not a core wild-type RB1 localization. RB1''s core compartment is the nucleus / nucleoplasm, where it carries out E2F repression and chromatin scaffolding (already ACCEPTed via the 17 R-HSA nucleoplasm TAS rows). Keeping on record at non-core priority is consistent with the analogous treatment of disease/ortholog-projected rows already in this file (e.g. PMID:24027266 GO:2001234 apoptosis row at line 1287 and PMID:19417128 GO:0120163 thermogenesis row at line 1296).'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9682712
  review:
    summary: TAS annotation for cytosolic localization sourced from the Reactome event 'nsp15 binds RB1', which describes SARS-CoV-1 non-structural protein 15 (nsp15) binding RB1 via its LXCXE/D motif and retaining RB1 in the cytosol (PMID:22301140 Bhardwaj et al. 2012). This is a viral-hijack mislocalization context — wild-type RB1 in uninfected cells is a chromatin-bound nuclear corepressor; cytosolic retention here is driven by viral nsp15 sequestration rather than reflecting a constitutive RB1 compartment.
    action: KEEP_AS_NON_CORE
    reason: 'Real biology in a disease/infection context (SARS-CoV-1 nsp15 sequesters wild-type RB1 in the cytosol via LXCXE/D-motif binding) but not a core wild-type RB1 localization in uninfected cells. RB1''s core compartment is the nucleus / nucleoplasm, where it carries out E2F repression and chromatin scaffolding (already ACCEPTed via the 17 R-HSA nucleoplasm TAS rows). Keeping on record at non-core priority is consistent with the analogous treatment of disease/ortholog-projected rows already in this file (e.g. PMID:24027266 GO:2001234 apoptosis row at line 1287 and PMID:19417128 GO:0120163 thermogenesis row at line 1296).'
- term:
    id: GO:0045786
    label: negative regulation of cell cycle
  evidence_type: ISS
  original_reference_id: PMID:24027266
  review:
    summary: 'ISS annotation citing PMID:24027266 (MiR-26b in Alzheimer''s disease — miR-26b directly represses RB1 to drive cell-cycle re-entry in postmitotic neurons). The source paper''s mechanism establishes RB1 as the canonical brake on cell-cycle progression: loss of RB1 via miR-26b targeting is sufficient to license aberrant cell-cycle re-entry. Negative regulation of cell cycle is the defining RB1 tumor-suppressor activity (PMID:7923370; deep research synthesis), already captured at higher specificity in this file via the GO:2000134 negative regulation of G1/S transition TAS row (PMID:19149898) ACCEPTed in batch 9 and the GO:0051726 regulation of cell cycle IEA row ACCEPTed in batch 5.'
    action: ACCEPT
    reason: 'Canonical RB1 cell-cycle-restriction function, well supported by experimental evidence already present in this file (PMID:7923370 RB-BRG1 cooperation; IDA/EXP rows in this annotation set) and by independent Reactome TAS rows previously ACCEPTed in PRs #440/#444. Mechanical ISS-canonical batch (batch 14 of #347).'
- term:
    id: GO:2001234
    label: negative regulation of apoptotic signaling pathway
  evidence_type: ISS
  original_reference_id: PMID:24027266
  review:
    summary: 'Downstream phenotype projected from mouse Rb1 ortholog: Rb1 affects apoptotic signaling sensitivity through E2F-target regulation (e.g. via BCL-2 family genes and cell-cycle/apoptosis crosstalk), but apoptotic-pathway regulation is a context-dependent consequence of RB1''s core E2F-repression / chromatin-scaffolding role rather than a primary RB1 function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0120163
    label: negative regulation of cold-induced thermogenesis
  evidence_type: ISS
  original_reference_id: PMID:19417128
  review:
    summary: 'Tissue-specific phenotype projected from mouse Rb1: Rb1 represses brown-adipocyte / thermogenic gene programs (Ucp1) in white adipose tissue (PMID:19417128), but cold-induced thermogenesis is a downstream metabolic consequence of RB1''s role in adipocyte differentiation/transcription control rather than a core RB1 function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0003180
    label: aortic valve morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Tissue-specific developmental phenotype projected from mouse Rb1 ortholog: Rb1-null mouse hearts exhibit cardiac valve defects, but this is a downstream developmental consequence of Rb1''s core role in E2F-mediated proliferation/differentiation control in cardiac neural crest and valvular interstitial cells, not a primary RB1 molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 loss can increase tissue inflammation as part of the senescence-associated secretory phenotype (SASP) and altered chromatin programs, but inflammatory regulation is a contextual consequence of RB1''s core E2F-repression / chromatin-scaffolding activity rather than a primary RB1 function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:1903055
    label: positive regulation of extracellular matrix organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 modulates ECM organization through transcriptional control of stromal/fibroblast programs, but ECM organization is a contextual consequence of RB1''s core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:1904028
    label: positive regulation of collagen fibril organization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Downstream tissue-level phenotype projected from mouse Rb1 ortholog: Rb1 affects collagen-fibril organization via transcriptional regulation of stromal programs, but collagen-fibril organization is a contextual consequence of RB1''s core role in cell-cycle / differentiation control rather than a primary molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:1904761
    label: negative regulation of myofibroblast differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: 'Tissue-specific phenotype projected from mouse Rb1 ortholog: Rb1 restricts myofibroblast differentiation programs in fibrotic contexts, but this is a downstream cell-fate consequence of RB1''s core E2F-repression / chromatin-scaffolding role rather than a primary molecular function.'
    action: KEEP_AS_NON_CORE
    reason: 'Real biology but a downstream / tissue-specific consequence of RB1''s core role in E2F-mediated G1/S repression and chromatin scaffolding (RB_A/RB_B pocket binding, HDAC1/SUV39H1/BRG1 recruitment) rather than a primary RB1 function. Kept on record at non-core priority. These rows are mouse Rb1 phenotypes projected to human via Ensembl/PANTHER (IEA GO_REF:0000107) and InterPro/UniProt ISS templates (GO_REF:0000024, plus PMIDs 19417128 and 24027266) - same non-core treatment as analogous tissue-specific ortholog projections in prior reviews.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:2730637
  review:
    summary: 'NAS annotation for nuclear localization derived from Taya et al. 1989 (PMID:2730637), a paper primarily about homology between the RB1 gene and L1 family repetitive sequences. The paper discusses DNA-binding properties of RB1 (which implicitly involves nuclear localization) but does not directly characterize subcellular localization. The NAS evidence is weak as a primary source, but the annotated function (nuclear localization) is independently and robustly supported by IDA evidence (PMID:1531329, PMID:20940255, PMID:17540172), TAS evidence (PMID:3657987 — the original Lee et al. 1987 nuclear-phosphoprotein paper), and 17 Reactome TAS rows on GO:0005654 nucleoplasm previously ACCEPTed (PR #444).'
    action: ACCEPT
    reason: 'The underlying annotation (nuclear localization) is one of the most robustly established RB1 facts, independently supported by multiple IDA/EXP/TAS rows from the foundational literature. The specific NAS source (PMID:2730637) is weak provenance individually, but consistent with the broader literature and not biologically wrong. Mechanical canonical-nuclear-localization batch (batch 10 of #347).'
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: NAS
  original_reference_id: PMID:2730637
  review:
    summary: 'NAS annotation derived from Taya et al. 1989 (PMID:2730637), a paper
      about homology between a region of the RB1 gene and L1-family repetitive sequences
      that only speculatively "discusses" possible DNA-binding properties of RB1;
      it does not characterize RB1 transcriptional regulation. The NAS source is therefore
      weak provenance for this term individually (the same weak-NAS PMID:2730637 situation
      was handled for the adjacent nuclear-localization row in batch 10). However,
      the underlying function — RB1 repression of E2F-dependent, DNA-templated transcription
      — is one of the most robustly established RB1 facts (core_functions[0]) and
      is directionally negative. The generic GO:0006355 is too broad; the specific
      child GO:0045892 (negative regulation of DNA-templated transcription) is the
      curation-preferred term and is independently supported by IDA/TAS evidence elsewhere
      in this file (PMID:1531329, PMID:12065415, PMID:10783144, PMID:19223331, PMID:19149898).'
    action: MODIFY
    reason: 'Essence (RB1 regulates DNA-templated transcription) is sound and canonical,
      but the NAS source is a sequence-homology paper and the generic GO:0006355 is
      too broad for RB1''s well-established negative/repressor activity. Replace with
      the specific GO:0045892 (negative regulation of DNA-templated transcription)
      already present in core_functions[0]; conservative MODIFY rather than REMOVE,
      consistent with the batch-10 handling of the weak-NAS PMID:2730637 localization
      row. Mechanical transcription-regulation batch (batch 20 of #347).'
    proposed_replacement_terms:
    - id: GO:0045892
      label: negative regulation of DNA-templated transcription
- term:
    id: GO:0061676
    label: importin-alpha family protein binding
  evidence_type: IPI
  original_reference_id: PMID:12695505
  review:
    summary: 'IPI annotation for importin-alpha family protein binding sourced from Fontes et al. 2003 (PMID:12695505). This study co-crystallized mammalian importin-alpha with a peptide corresponding to the bipartite nuclear localization sequence of human retinoblastoma protein, defining the structural basis by which importin-alpha specifically recognizes the RB1 NLS. This is genuine, specific (informative) evidence that RB1 binds the importin-alpha nuclear-import receptor.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1-importin-alpha binding is correctly and specifically supported by the PMID:12695505 co-crystal structure and is informative rather than generic protein binding, but it represents the nuclear-import transport mechanism that delivers RB1 to its compartment rather than the defining nuclear E2F-corepressor / chromatin-scaffold activity in core_functions[0]. Kept on record at non-core priority, consistent with the file''s treatment of localization/transport mechanisms (e.g., GO:0005737 cytoplasm KEEP_AS_NON_CORE) relative to the core corepressor function. Mechanical binding-partner-MF batch (batch 22 of #347).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: PMID:8245034
  review:
    summary: 'IDA annotation for nucleoplasmic localization sourced from Pahel et al. 1993 (PMID:8245034), an HPV16 E7 biochemistry paper. E7 is a "nuclear phosphoprotein" that binds RB1 "avidly and specifically" and can dissociate the E2F transcription factor from RB1 in vitro. The biochemistry of the E7–RB1 interaction is performed on nuclear RB1, supporting RB1 nucleoplasmic localization. Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is independently supported by 17 Reactome TAS rows on GO:0005654 already ACCEPTed (PR #444), by IDA evidence (PMID:17540172 in PR #499, GO_REF:0000052 HPA in this batch), and by canonical IEA propagations ACCEPTed in PR #461.'
    action: ACCEPT
    reason: 'Canonical RB1 nucleoplasmic localization, well supported by experimental evidence already present in this file (17 Reactome TAS rows ACCEPTed in PR #444; IDA from PMID:17540172 ACCEPTed in PR #499). The E7-RB1 interaction characterized in PMID:8245034 is well established to occur in the nucleus where RB1 binds chromatin. Mechanical canonical-nuclear-localization batch (batch 10 of #347).'
- term:
    id: GO:0035189
    label: Rb-E2F complex
  evidence_type: IDA
  original_reference_id: PMID:8245034
  review:
    summary: 'Pahel et al. 1993 (PMID:8245034) characterizes purified HPV16 E7 and
      shows it "binds the retinoblastoma protein avidly and specifically, and it can
      dissociate the E2F transcription factor when assayed in vitro." Demonstrating
      that E7 dissociates E2F from RB1 directly evidences the pre-existing RB1-E2F
      complex. The Rb-E2F complex is the namesake, canonical RB1 mechanism: the RB_A/RB_B
      pocket engages activator E2F1/2/3 to occupy E2F target promoters (PMID:7923370;
      deep research synthesis). This exact GO:0035189 term is already independently
      ACCEPTed on IBA (GO_REF:0000033, batch 6), IPI (PMID:16360038, batch 17), and
      IEA (PR #461) evidence elsewhere in this file.'
    action: ACCEPT
    reason: 'Canonical core RB1 function — the Rb-E2F complex is the defining RB1 mechanism,
      independently and robustly supported across IBA/IPI/IEA evidence already ACCEPTed
      on this exact term in this file. Same canonical-Rb-E2F ACCEPT precedent as the
      batch-17 PMID:16360038 structural rows. Mechanical canonical-Rb-E2F batch (batch
      19 of #347).'
- term:
    id: GO:0097718
    label: disordered domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:8245034
  review:
    summary: 'Pahel et al. 1993 (PMID:8245034) is an HPV16 E7 biochemistry paper showing
      E7 (an intrinsically disordered viral oncoprotein) binds RB1 and dissociates
      E2F. GO:0097718 disordered domain specific binding is a generic, uninformative
      binding term that does not capture RB1''s specific LxCxE-cleft / RB_A-RB_B pocket
      adapter biology, and the paper does not set out to characterize RB1''s binding
      specificity for disordered domains as such. The informative interaction from
      this paper is already captured by the ACCEPTed GO:0035189 (Rb-E2F complex) row
      from the same reference.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'Generic, uninformative binding term for RB1''s well-characterized adapter/scaffolding
      biology, derived from an HPV E7 biochemistry paper rather than a study of RB1
      disordered-domain binding specificity. Conservative demotion consistent with
      the uniform GO:0005515 protein-binding precedent in this same review and the
      batch-18 PMID:16360038 generic-binding handling (GO:0042802 / GO:0051219). Mechanical
      generic-binding batch (batch 19 of #347).'
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:25100735
  review:
    summary: 'IMP annotation from Miles et al. 2014 (PMID:25100735), which shows that
      NANOS (NANOS1/NANOS3) "is directly repressed by pRb/E2F in flies and humans."
      siRNA depletion of the pocket proteins (including pRb) from human BJ fibroblasts
      produced "a strong up-regulation in the expression of the NANOS1 and NANOS3
      genes," and ChIP showed that dREAM (E2F4/p107/p130) occupancy at the NANOS1
      promoter is pRb-dependent. This is direct functional (IMP) evidence that RB1
      negatively regulates target-gene expression — a canonical instance of RB1''s
      defining transcriptional corepressor activity (core_functions[0]), concordant
      with the GO:0045892 IDA/TAS rows ACCEPTed elsewhere in this file (PMID:12065415,
      PMID:10783144, PMID:19223331, PMID:19149898).'
    action: ACCEPT
    reason: 'Canonical RB1 transcriptional repressor activity — pRb directly represses
      NANOS1/3 expression (IMP via pocket-protein depletion plus dREAM-promoter ChIP).
      Maps to core_functions[0] (Rb-E2F transcriptional corepressor) and is independently
      supported by the GO:0045892 negative-regulation rows already ACCEPTed in this
      file. Mechanical transcription-regulation batch (batch 20 of #347).'
- term:
    id: GO:2000679
    label: positive regulation of transcription regulatory region DNA binding
  evidence_type: IDA
  original_reference_id: PMID:25100735
  review:
    summary: 'IDA annotation from Miles et al. 2014 (PMID:25100735). ChIP experiments
      show that pRb stabilizes binding of the dREAM repressor components (E2F4, p107,
      p130) at the NANOS1 promoter: "these observations suggest that pRb stabilizes
      dREAM-binding to the NANOS1 promoter," and "the binding of these dREAM components
      to the NANOS1 promoter was dramatically reduced by knockdown of pRb." This biologically
      supports GO:2000679 (RB1 positively regulating occupancy of a transcription
      regulatory region by the repressor complex); the finding is correct and not
      an over-annotation. However, it describes a fine-grained downstream mechanistic
      consequence of RB1''s repressor scaffold rather than RB1''s core function; the
      core activity (transcriptional corepression / negative regulation of DNA-templated
      transcription) is already captured in core_functions[0].'
    action: KEEP_AS_NON_CORE
    reason: 'Biologically correct and IDA-supported (pRb stabilizes dREAM/E2F4 occupancy
      at the NANOS1 promoter), but a specific mechanistic detail of the repressor-scaffold
      mechanism rather than a core RB1 function. Retain as non-core; the core repressor
      activity is represented by core_functions[0] and the GO:0045892 rows. Mechanical
      transcription-regulation batch (batch 20 of #347).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12037672
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0008024
    label: cyclin/CDK positive transcription elongation factor complex
  evidence_type: IDA
  original_reference_id: PMID:12037672
  review:
    summary: 'IDA cellular-component annotation citing Simone et al. 2002 (PMID:12037672),
      "Physical interaction between pRb and cdk9/cyclinT2 complex." That paper demonstrates
      an in vitro and in vivo physical interaction between pRb (C-terminal domain, residues
      835-928) and the cdk9/cyclinT2 complex, and maps cdk9-mediated phosphorylation
      of the pRb C-terminus (S795/S807/S811). pRb is thus an interactor and phosphorylation
      substrate of cdk9/cyclinT2 (P-TEFb), not a constitutive structural subunit of
      the cyclin/CDK positive transcription elongation factor complex (GO:0008024).
      The authors themselves describe pRb and cdk9/cyclinT2 as "located in a nuclear
      multiprotein complex," i.e. a transient/regulatory association, which does not
      establish stable membership of the P-TEFb elongation factor complex itself.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'The cited evidence supports a physical interaction with and phosphorylation
      by cdk9/cyclinT2, but a CC complex-membership term (GO:0008024) implies pRb is
      a stable subunit of P-TEFb, which the source does not establish — pRb is a substrate/interactor,
      not a core subunit. Conservative demotion (the association is real, so not REMOVE)
      consistent with the in-file handling of interaction-derived over-specific terms
      (e.g. the GO:0042802/PMID:16360038 batch-17 demotion). The genuine pRb-cdk9 interaction
      is better represented as a binding/phospho-substrate relationship than as P-TEFb
      complex membership.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15107404
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-188191
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2172666
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9018017
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9659820
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9686969
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9686980
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9768288
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-8985474
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-NUL-8985490
  review:
    summary: TAS annotation for nucleoplasmic localization sourced from a Reactome pathway event. RB1 is a chromatin-bound nuclear corepressor that occupies E2F-target gene promoters in the nucleoplasm; nucleoplasmic localization of hypophosphorylated active RB1 is well established and is the compartment in which RB1 binds E2F1/2/3 and recruits chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4) (PMID:7923370; deep research synthesis).
    action: ACCEPT
    reason: 'Nucleoplasmic localization is the canonical compartment for active hypophosphorylated RB1 and is well supported across the literature. Each of the 17 Reactome TAS events is a separate nucleoplasm annotation describing the same localization context, so they are mechanically consolidated to ACCEPT with a uniform template (BRAF PR #440 / KRAS PR #349 precedent for analogous Reactome TAS localization sweeps).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7651420
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:12065415
  review:
    summary: 'IDA annotation supporting RB1''s canonical role as a negative regulator of DNA-templated transcription, sourced from the Prohibitin/Brg-1/Brm paper (PMID:12065415) which directly shows that pRb-mediated repression of E2F-target gene promoters and the resulting cell-growth suppression require the SWI/SNF chromatin remodelers BRG1/SMARCA4 and BRM. Negative regulation of DNA-templated transcription is RB1''s defining transcriptional activity at E2F-target promoters (PMID:7923370; deep research synthesis), already captured in core_functions[0] (Rb-E2F transcriptional corepressor) and independently supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347).'
    action: ACCEPT
    reason: 'Canonical RB1 corepressor activity, well anchored to the pRb-E2F repressor model and to RB1''s SWI/SNF (BRG1/BRM) chromatin-remodeler partnership already supported elsewhere in this file (GO:0006338 chromatin remodeling TAS PMID:19149898 ACCEPTed, GO:0016514 SWI/SNF complex TAS ACCEPTed). The PMID:12065415 paper provides direct experimental evidence (IDA) for pRb-mediated repression at E2F-target promoters via prohibitin/SWI/SNF cooperation. Mechanical canonical-corepressor IDA batch (batch 13 of #347) — 3 IDA rows on GO:0045892 from primary literature uniformly consolidated to ACCEPT.'
- term:
    id: GO:0007346
    label: regulation of mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:20551165
  review:
    summary: 'IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB depletion slows mitotic progression and promotes aneuploidy through compromised centromere function and chromosome cohesion (CAP-D3/condensin II mislocalization, merotelic attachment, lagging chromosomes). Real RB1 biology — RB1 loss alters mitotic timing/fidelity — but this is a non-cell-cycle-arrest mitotic phenotype downstream of RB1''s primary G1/S corepressor activity, and "regulation of mitotic cell cycle" is a very broad parent term that does not capture the specific Manning et al. mitotic-fidelity mechanism.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1''s primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.'
- term:
    id: GO:0031134
    label: sister chromatid biorientation
  evidence_type: IMP
  original_reference_id: PMID:20551165
  review:
    summary: 'IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB depletion causes merotelic kinetochore-microtubule attachments and failure of chromosome congression — the cellular consequence of compromised centromere/cohesion architecture (CAP-D3/condensin II mislocalization, increased intercentromeric distance). Sister chromatid biorientation defects directly explain the lagging chromosomes and missegregation phenotype reported in the paper. Real RB1 biology but a non-core mitotic-fidelity role rather than RB1''s defining transcriptional corepressor activity.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1''s primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.'
- term:
    id: GO:0034088
    label: maintenance of mitotic sister chromatid cohesion
  evidence_type: IMP
  original_reference_id: PMID:20551165
  review:
    summary: 'IMP annotation from Manning et al. 2010 (PMID:20551165), which directly showed that pRB depletion compromises centromeric chromosome cohesion (increased intercentromeric distance, deformed centromeric structure) via mislocalization of CAP-D3/condensin II. The paper explicitly identifies cohesion maintenance at centromeres as a function disrupted by pRB loss. Real RB1 biology — RB1 is required for maintenance of mitotic centromere cohesion via the condensin II pathway — but this is a non-core mitotic-fidelity role rather than RB1''s defining transcriptional corepressor activity.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1''s primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.'
- term:
    id: GO:0045842
    label: positive regulation of mitotic metaphase/anaphase transition
  evidence_type: IMP
  original_reference_id: PMID:20551165
  review:
    summary: 'IMP annotation from Manning et al. 2010 (PMID:20551165), which showed that pRB-depleted cells experience mitotic delay with lagging chromosomes following compromised centromere cohesion and merotelic attachment. The "positive regulation of metaphase/anaphase transition" framing reflects the paper''s observation that loss of pRB impairs timely progression through metaphase/anaphase due to faulty kinetochore-microtubule attachments and the resulting spindle checkpoint engagement. Real RB1 biology — RB1 supports timely metaphase-to-anaphase progression by maintaining the centromere/cohesion architecture required for proper kinetochore attachment — but this is a non-core mitotic-fidelity role rather than RB1''s defining transcriptional corepressor activity.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1''s primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.'
- term:
    id: GO:0071459
    label: protein localization to chromosome, centromeric region
  evidence_type: IMP
  original_reference_id: PMID:20551165
  review:
    summary: 'IMP annotation from Manning et al. 2010 (PMID:20551165), which directly showed that pRB depletion compromises centromeric localization of CAP-D3/condensin II — the most specific molecular finding of the paper and the mechanistic basis for the downstream cohesion/segregation defects. RB1 is required for proper recruitment of the condensin II complex to centromeric chromatin. Real RB1 biology — RB1 supports centromeric protein localization via condensin II recruitment — but this is a non-core mitotic-fidelity role rather than RB1''s defining transcriptional corepressor activity.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s contribution to mitotic centromere/cohesion fidelity (Manning 2010 PMID:20551165) is a real but non-core mitotic role that explains a downstream cancer consequence (CIN/aneuploidy in RB1-null tumors) rather than defining RB1''s primary molecular activity. The canonical RB1 core function (Rb-E2F complex assembly, negative regulation of G1/S transition, chromatin-bound transcription corepression with HDAC1/SUV39H1/BRG1) is already captured by direct experimental evidence elsewhere in this file (PMID:7923370 IDA, PMID:16360038 IPI on GO:0035189). Mechanical PMID:20551165 single-paper batch (batch 11 of #347) — all 6 IMP rows from this paper consolidated to KEEP_AS_NON_CORE with a uniform template.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20870719
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16964284
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11571652
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10613832
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:19223331
  review:
    summary: 'IDA annotation supporting RB1''s canonical role as a negative regulator of DNA-templated transcription, sourced from the HMGB1/HMGB2 topoisomerase IIalpha paper (PMID:19223331) which characterizes pRb-mediated repression of the human topoisomerase IIalpha promoter and the antagonistic activity of HMGB1/HMGB2 on this repression. The paper provides direct experimental evidence (IDA) for pRb-mediated repression of an endogenous promoter. Negative regulation of DNA-templated transcription is RB1''s defining transcriptional activity (PMID:7923370; deep research synthesis), already captured in core_functions[0] (Rb-E2F transcriptional corepressor) and independently supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347).'
    action: ACCEPT
    reason: 'Canonical RB1 corepressor activity demonstrated by direct experimental evidence (IDA) on an endogenous target promoter (TOP2A). PMID:19223331 frames pRb as a repressor of the human topoisomerase IIalpha promoter that HMGB1/HMGB2 counteract. Consistent with RB1''s defining corepressor activity already captured by core_functions[0] and supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347) and analogous IDA/IMP rows elsewhere in this file. Mechanical canonical-corepressor IDA batch (batch 13 of #347) — 3 IDA rows on GO:0045892 from primary literature uniformly consolidated to ACCEPT.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7503932
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0007265
    label: Ras protein signal transduction
  evidence_type: IEP
  original_reference_id: PMID:9054499
  review:
    summary: 'IEP annotation citing Serrano et al. 1997 (PMID:9054499), "Oncogenic
      ras provokes premature cell senescence associated with accumulation of p53 and
      p16INK4a." That paper establishes that oncogenic RAS induces a permanent G1 arrest
      (oncogene-induced senescence) accompanied by accumulation of p53 and p16INK4a,
      with p16/p53 inactivation preventing the arrest. RB1 is not characterized in this
      study as a Ras-pathway transducer; its only relationship to this work is as a
      downstream effector of the p16INK4a-CDK4/6 arm engaged during RAS-induced senescence.
      GO:0007265 Ras protein signal transduction denotes the small-GTPase Ras signaling
      relay itself (GEF/GAP/effector cascade), of which RB1 is categorically not a member.'
    action: REMOVE
    reason: 'Categorical functional-class mismatch: RB1 is a chromatin-bound transcriptional
      corepressor / G1-S effector, not a component or regulator of the Ras GTPase signal-transduction
      cascade (GO:0007265). The IEP source (PMID:9054499) is a p16/p53 oncogene-induced-senescence
      paper that does not interrogate RB1''s role in Ras signaling at all. Per the schema,
      a wrong functional class (REMOVE, "unlikely to be correct based on combined evidence")
      is distinct from over-granularity (MARK_AS_OVER_ANNOTATED); this is the former,
      following the in-file batch-22 GO:0031625/PMID:10944455 REMOVE precedent for an
      evidence-class mismatch. RB1''s genuine downstream role in RAS/oncogene-induced
      senescence would belong as a senescence/cell-cycle annotation with its own source,
      not as Ras signal transduction.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15542589
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10783144
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:10783144
  review:
    summary: 'IDA annotation supporting RB1''s canonical role as a negative regulator of DNA-templated transcription, sourced from the Che-1/AATF paper (PMID:10783144) — "Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which interacts with and affects the growth suppression function of Rb." The paper demonstrates pRb''s growth-suppression activity at Pol II-driven gene programs and shows that Che-1 (AATF, the human Bfr2 homolog) modulates this activity through its interaction with Rb. Negative regulation of DNA-templated transcription is RB1''s defining transcriptional activity (PMID:7923370; deep research synthesis), already captured in core_functions[0] (Rb-E2F transcriptional corepressor) and independently supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347).'
    action: ACCEPT
    reason: 'Canonical RB1 corepressor activity demonstrated by direct experimental evidence (IDA) on Pol II-driven growth-suppression promoter activity, in the context of the Che-1/AATF interaction with Rb. Consistent with RB1''s defining corepressor activity already captured by core_functions[0] and supported by TAS PMID:19149898 (ACCEPTed in batch 9 of #347) and analogous IDA rows on this term elsewhere in this file. Mechanical canonical-corepressor IDA batch (batch 13 of #347) — 3 IDA rows on GO:0045892 from primary literature uniformly consolidated to ACCEPT.'
- term:
    id: GO:0051219
    label: phosphoprotein binding
  evidence_type: IPI
  original_reference_id: PMID:16360038
  review:
    summary: 'Rubin et al. 2005 (PMID:16360038, Cell) demonstrates that CDK phosphorylation
      of RB1 itself drives E2F release: phosphorylation at S788/S795 directly destabilizes
      one set of RbC-E2F-DP contacts, while phosphorylation at T821/T826 induces an
      intramolecular RbC-pocket interaction that destabilizes the remaining contacts.
      RB1 is the phosphoprotein in this mechanism and phosphorylation promotes dissociation;
      the paper does not show RB1 binding to a phosphorylated partner protein. GO:0051219
      phosphoprotein binding (binding a phosphorylated protein) is therefore not supported
      by this evidence and mischaracterizes the phospho-regulation-of-RB1 / E2F-release
      mechanism the paper actually establishes.'
    action: MARK_AS_OVER_ANNOTATED
    reason: 'The cited paper characterizes phosphorylation OF RB1 driving E2F release,
      the opposite of RB1 binding a phosphoprotein partner; the term is unsupported
      by this source. Conservative demotion consistent with the GO:0005515 precedent
      in this review and the batch-17 handling of PMID:16360038.'
- term:
    id: GO:0045445
    label: myoblast differentiation
  evidence_type: IMP
  original_reference_id: PMID:15541338
  review:
    summary: 'IMP annotation citing Sekimata & Homma 2004 (PMID:15541338), "Regulation
      of Rb gene expression by an MBD2-interacting zinc finger protein MIZF during myogenic
      differentiation." The study shows MIZF represses Rb transcription; forced MIZF
      expression in C2C12 myoblasts lowers Rb (and myogenin/Troponin-T) and blocks differentiation
      into multinucleated myotubes, indicating that induction of Rb expression is required
      for myogenic differentiation. RB1''s pro-differentiation role in the myogenic
      lineage is well established (deep research synthesis; corroborated by PMID:9448006
      discussion noting nonphosphorylated pRB promotes myocyte differentiation). The
      evidence here is somewhat indirect (it manipulates MIZF rather than RB1 directly),
      but the conclusion that Rb is needed for myoblast differentiation is consistent
      with the broader literature.'
    action: KEEP_AS_NON_CORE
    reason: 'RB1''s role in myoblast/myogenic differentiation is real and literature-supported
      but is a lineage-specific developmental context downstream of the defining Rb-E2F
      cell-cycle-exit/transcriptional-corepressor activity (core_functions[0]; ACCEPTed
      GO:0051726, GO:0045892 rows), not a core molecular function. Retained on record
      as non-core, consistent with the GO:0032502 developmental process KEEP_AS_NON_CORE
      decision in this batch and the broader non-core differentiation/senescence framing
      in the deep research synthesis.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17540172
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:10944455
  review:
    summary: 'IPI annotation for ubiquitin protein ligase binding citing Wen & Ao 2000 (PMID:10944455). That paper characterizes RBP95, a novel 838-residue basic-region leucine-zipper protein that binds pRb through a conserved LXCXE motif engaging the entire pocket region, and proposes RBP95 functions in RNA polymerase II-mediated transcription/processing. RBP95 is not a ubiquitin protein ligase and the study describes no ubiquitin-ligase activity, ubiquitination, or E3-ligase interaction; the cited evidence therefore does not support the term GO:0031625 ubiquitin protein ligase binding.'
    action: REMOVE
    reason: 'The cited source does not support GO:0031625: PMID:10944455 (Wen & Ao 2000) characterizes RBP95, an LXCXE-motif basic-region leucine-zipper transcription-associated partner with no ubiquitin-ligase activity, RING/HECT domain, or ubiquitination assay. The evidence gap is categorical (a bZIP transcription partner vs. a ubiquitin protein ligase are unrelated functional classes), not a matter of over-granularity, so per the schema this is REMOVE ("unlikely to be correct based on combined evidence") rather than MARK_AS_OVER_ANNOTATED ("not entirely wrong... over-annotation"). This differs from the in-file GO:0042802/PMID:16360038 precedent, where the evidence was within the correct functional class but heterotypic rather than homotypic (a scope issue). If separate evidence exists that RB1 binds a ubiquitin ligase, it belongs as a new annotation with its own source. Mechanical binding-partner-MF batch (batch 22 of #347).'
- term:
    id: GO:0006338
    label: chromatin remodeling
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes pRb-mediated chromatin remodeling at E2F-target promoters via recruitment of BRM, BRG1/SMARCA4 (SWI/SNF catalytic subunit), and HDAC1. Chromatin remodeling is a canonical RB1 BP activity supported by extensive primary literature (PMID:7923370; deep research synthesis).'
    action: ACCEPT
    reason: 'Chromatin remodeling via SWI/SNF and histone-deacetylase recruitment is a canonical mechanism for RB1-mediated E2F repression. PMID:19149898 directly states pRb "can repress gene transcription at least partly by remodelling chromatin structure through its interactions with proteins such as HDAC1, BRM and BRG1." Mechanical TAS batch (batch 9 of #347).'
- term:
    id: GO:0016514
    label: SWI/SNF complex
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes RB1 association with the SWI/SNF chromatin-remodeling complex via the catalytic subunits BRM and BRG1/SMARCA4. The RB1-BRG1 interaction recruits SWI/SNF to E2F-responsive promoters to enhance pRb transcriptional repressor activity (cited refs 4 and 5 in Becker et al.).'
    action: ACCEPT
    reason: 'RB1''s recruitment of SWI/SNF to E2F-target chromatin is one of the canonical chromatin-coregulator interactions for RB1, with direct biochemical support across multiple primary papers. PMID:19149898 explicitly describes "BRG1, as the catalytic core of the SWI/SNF chromatin remodelling complex, the interaction between BRG1 and pRb was proposed to recruit the complex to E2F responsive promoters." Mechanical TAS batch (batch 9 of #347).'
- term:
    id: GO:0035189
    label: Rb-E2F complex
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which describes "active pRb-E2F transcriptional repressor complexes that silence genes required for S-phase entry." Rb-E2F complex membership is the defining biochemical complex for RB1''s tumor-suppressor function and is already independently captured in this file by IBA (PR #490) and IPI (PMID:8245034) evidence.'
    action: ACCEPT
    reason: 'Rb-E2F complex membership is the defining biochemical complex for RB1''s tumor-suppressor activity at the G1/S restriction point. PMID:19149898 directly anchors this annotation to the active pRb-E2F repressor complex framework. Mechanical TAS batch (batch 9 of #347).'
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews pRb as a transcriptional corepressor that silences E2F-target genes via chromatin remodeling. Negative regulation of DNA-templated transcription is the general BP parent of the canonical pRb-E2F repression activity (GO:0000122 is the Pol II-specific child) and is already supported by IDA evidence on PMID:12065415 and PMID:10783144 elsewhere in this file.'
    action: ACCEPT
    reason: 'Negative regulation of DNA-templated transcription is a canonical RB1 activity, well anchored to the pRb-E2F repressor model that PMID:19149898 reviews. Mechanical TAS batch (batch 9 of #347).'
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: TAS
  original_reference_id: PMID:19149898
  review:
    summary: 'TAS annotation citing Becker et al. 2009 (PMID:19149898), which reviews the canonical p16INK4a–Cyclin D-CDK4/6–pRb–E2F G1/S switch. Regulation of cell cycle is a canonical RB1 BP, already captured in this file via IEA propagation (GO_REF:0000120) and by multiple direct experimental rows on G1/S regulators.'
    action: ACCEPT
    reason: 'Regulation of the cell cycle is one of the defining RB1 tumor-suppressor functions, central to the existing core_functions[0] block (G1/S restriction). PMID:19149898 directly anchors RB1 to the canonical CDK4/6-cyclin D-pRb-E2F G1/S switch. Mechanical TAS batch (batch 9 of #347).'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11073990
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9448006
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0016605
    label: PML body
  evidence_type: IDA
  original_reference_id: PMID:9448006
  review:
    summary: 'IDA annotation citing Alcalay et al. 1998 (PMID:9448006), "The promyelocytic
      leukemia gene product (PML) forms stable complexes with the retinoblastoma protein."
      By immunofluorescence the authors directly demonstrate that endogenous nonphosphorylated
      (hypophosphorylated) pRB colocalizes with PML within PML nuclear bodies (NBs),
      and that PML and pRB form stable complexes in vivo via the pRB pocket region;
      PML-RARalpha expression delocalizes pRB from the NBs. This is direct experimental
      evidence (IDA) for localization of a fraction of hypophosphorylated pRB to PML
      bodies. PML-NB localization is a specific subnuclear context linked to growth
      suppression / differentiation / senescence, distinct from the canonical nucleoplasmic
      E2F-target-promoter localization that constitutes RB1''s core compartment.'
    action: KEEP_AS_NON_CORE
    reason: 'Directly demonstrated (IDA) localization of hypophosphorylated pRB to PML
      nuclear bodies is real but represents a specialized, low-stoichiometry (~0.5-1%)
      subnuclear pool in a growth-suppressive/differentiation context, not the canonical
      nucleoplasmic compartment where active RB1 occupies E2F-target promoters (captured
      by the ACCEPTed GO:0005654 nucleoplasm Reactome TAS rows). Retained as a real
      non-core localization, same precedent as the GO:0005819 spindle (batch 15, #551)
      and GO:0005737 cytoplasm KEEP_AS_NON_CORE rows.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9395244
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0019900
    label: kinase binding
  evidence_type: IDA
  original_reference_id: PMID:16286473
  review:
    summary: 'IDA annotation for kinase binding sourced from Los et al. 2006 (PMID:16286473,
      J Biol Chem). The paper demonstrates that hypophosphorylated pRB binds directly
      to the lipid kinase diacylglycerol kinase zeta (DGKzeta) in vitro and in vivo
      (pRB had previously been shown to bind phosphatidylinositol-4-phosphate 5-kinases),
      with binding dependent on pRB phosphorylation status [PMID:16286473 "DGKzeta
      ... interacts with pRB in vitro and in vivo. Binding of DGKzeta to pRB is dependent
      on the phosphorylation status of pRB, since only hypophosphorylated pRB interacts
      with DGKzeta"]. GO:0019900 is appropriately informative and preferred over the
      generic GO:0005515 protein binding rows uniformly demoted elsewhere in this file,
      and the direct binding is well supported. This lipid-kinase effector interaction
      is a peripheral, non-core relationship — RB1''s core molecular function is E2F-DP
      pocket binding and chromatin-corepressor recruitment (core_functions[0]), not
      lipid-signaling enzyme binding.'
    action: KEEP_AS_NON_CORE
    reason: 'Direct, phosphorylation-dependent pRB–DGKzeta binding is well supported
      by IDA evidence in PMID:16286473, and GO:0019900 (kinase binding) is appropriately
      informative (preferred over generic protein binding per CLAUDE.md). Retained
      as non-core because the DGKzeta/lipid-kinase interaction is a downstream effector
      relationship peripheral to RB1''s canonical E2F-pocket/chromatin tumor-suppressor
      function. Kinase-interaction cluster (batch 21 of #347).'
- term:
    id: GO:0043550
    label: regulation of lipid kinase activity
  evidence_type: IDA
  original_reference_id: PMID:16286473
  review:
    summary: 'IDA annotation for regulation of lipid kinase activity sourced from Los
      et al. 2006 (PMID:16286473, J Biol Chem). The paper shows that pRB (and the related
      pocket proteins p107 and p130) specifically and potently STIMULATE the activity
      of the lipid kinase DGKzeta in vitro [PMID:16286473 "we found that pRB, p107,
      and p130 potently stimulate DGKzeta activity in vitro"], proposing DGKzeta as
      a downstream effector of pRB that regulates nuclear diacylglycerol/phosphatidic
      acid levels. The recorded term GO:0043550 (regulation of lipid kinase activity)
      is directionally unspecified and therefore too general for this evidence, which
      demonstrates positive regulation/stimulation specifically. This is a peripheral,
      non-core lipid-signaling effector role rather than RB1''s canonical E2F/cell-cycle
      function.'
    action: MODIFY
    reason: 'Essence (RB1 regulates a lipid kinase) is sound and supported by IDA in
      PMID:16286473, but the data specifically show stimulation/activation of DGKzeta,
      so the directionally-neutral GO:0043550 is too general. Replace with the specific
      child GO:0090218 (positive regulation of lipid kinase activity); conservative
      MODIFY rather than ACCEPT-as-is, consistent with the batch-20 handling of the
      over-general GO:0006355 transcription row. Non-core lipid-signaling effector
      role. Kinase-interaction cluster (batch 21 of #347).'
    proposed_replacement_terms:
    - id: GO:0090218
      label: positive regulation of lipid kinase activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9858607
  review:
    summary: 'This protein binding annotation records a physical interaction (IPI) but uses the uninformative generic term GO:0005515. RB1 has dozens of well-characterized binding partners — activator E2Fs (E2F1/2/3) via the RB_A/RB_B pocket, chromatin corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, DNA methyltransferases), DNA repair factors (Ku70/Ku80), and lineage-specific transcription cofactors (RUNX2, AR, CEBPD, PU.1) — and specific MF terms should be preferred per CLAUDE.md curation guidelines.'
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic 'protein binding' is uninformative for RB1's well-characterized adapter/scaffolding biology. Same precedent as BAG3 (#313) and KRAS (#349) where all GO:0005515 IPI rows were uniformly demoted.
- term:
    id: GO:0006469
    label: negative regulation of protein kinase activity
  evidence_type: IPI
  original_reference_id: PMID:9858607
  review:
    summary: 'IPI annotation for negative regulation of protein kinase activity sourced
      from Siegert & Robbins 1999 (PMID:9858607, Mol Cell Biol). The large pocket of
      Rb binds directly to the TFIID subunit TAFII250 (TAF1) and dose-responsively
      inhibits its intrinsic, bipartite kinase activity — both TAFII250 autophosphorylation
      and transphosphorylation of the RAP74 subunit of TFIIF [PMID:9858607 "Rb is able
      to inhibit the kinase activity of immunopurified and gel-purified recombinant
      TAFII250. Rb inhibits the autophosphorylation of TAFII250 as well as its phosphorylation
      of the RAP74 subunit of TFIIF in a dose-responsive manner"]. Tumor-derived Rb
      pocket mutants are functionally defective for this kinase inhibition despite
      retaining binding [PMID:9858607 "two different tumor-derived Rb pocket mutants,
      C706F and Deltaex22, are functionally defective for kinase inhibition, even though
      they are able to bind the amino terminus of TAFII250"], linking the activity
      to the tumor-suppressor pocket. GO:0006469 is well supported and specific. The
      authors frame this as a novel, promoter-context-specific transcriptional-regulation
      mechanism — a peripheral facet rather than RB1''s canonical E2F-masking/chromatin-corepressor
      core function.'
    action: KEEP_AS_NON_CORE
    reason: 'Direct, dose-responsive Rb inhibition of TAFII250 (TAF1) kinase activity
      is well supported in PMID:9858607, and GO:0006469 (negative regulation of protein
      kinase activity) is specific and accurate. Retained as non-core because the authors
      frame it as a novel, promoter-specific accessory mechanism of transcriptional
      repression, distinct from RB1''s canonical E2F-pocket/chromatin-corepressor core
      function (core_functions[0]). Kinase-interaction cluster (batch 21 of #347).'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10613832
  title: Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas.
  findings: []
- id: PMID:10779361
  title: Mutagenesis of the pRB pocket reveals that cell cycle arrest functions are separable from binding to viral oncoproteins.
  findings: []
- id: PMID:10783144
  title: Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which interacts with and affects the growth suppression function of Rb.
  findings: []
- id: PMID:10944455
  title: RBP95, a novel leucine zipper protein, binds to the retinoblastoma protein.
  findings: []
- id: PMID:11073990
  title: A novel Rb- and p300-binding protein inhibits transactivation by MyoD.
  findings: []
- id: PMID:11268000
  title: Ebp1, an ErbB-3 binding protein, interacts with Rb and affects Rb transcriptional regulation.
  findings: []
- id: PMID:11571652
  title: The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein.
  findings: []
- id: PMID:12037672
  title: Physical interaction between pRb and cdk9/cyclinT2 complex.
  findings: []
- id: PMID:12065415
  title: Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth.
  findings: []
- id: PMID:12434308
  title: Protein Phosphatase 1 binds strongly to the retinoblastoma protein but not to p107 or p130 in vitro and in vivo.
  findings: []
- id: PMID:12502741
  title: Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor.
  findings: []
- id: PMID:12598654
  title: Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation.
  findings: []
- id: PMID:12695505
  title: Structural basis for the specificity of bipartite nuclear localization sequence binding by importin-alpha.
  findings: []
- id: PMID:12743606
  title: The adenovirus E1A oncoprotein recruits the cellular TRRAP/GCN5 histone acetyltransferase complex.
  findings: []
- id: PMID:12813456
  title: Interaction of the HPV E7 proteins with the pCAF acetyltransferase.
  findings: []
- id: PMID:1331501
  title: Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins.
  findings: []
- id: PMID:14555653
  title: LEK1 is a potential inhibitor of pocket protein-mediated cellular processes.
  findings: []
- id: PMID:14645241
  title: Interactions between activating signal cointegrator-2 and the tumor suppressor retinoblastoma in androgen receptor transactivation.
  findings: []
- id: PMID:15084261
  title: Cyclin C/cdk3 promotes Rb-dependent G0 exit.
  findings: []
- id: PMID:15107404
  title: Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity.
  findings: []
- id: PMID:1531329
  title: The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F.
  findings: []
- id: PMID:15541338
  title: Regulation of Rb gene expression by an MBD2-interacting zinc finger protein MIZF during myogenic differentiation.
  findings: []
- id: PMID:15542589
  title: LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at chromosome 3p21.3, binds pRB and represses E2F-driven transcription.
  findings: []
- id: PMID:16061792
  title: Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600.
  findings: []
- id: PMID:16249186
  title: Structure of the human Papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor.
  findings: []
- id: PMID:16286473
  title: The retinoblastoma family proteins bind to and activate diacylglycerol kinase zeta.
  findings: []
- id: PMID:16360038
  title: 'Structure of the Rb C-terminal domain bound to E2F1-DP1: a mechanism for phosphorylation-induced E2F release.'
  findings: []
- id: PMID:16374512
  title: DNA-damage-responsive acetylation of pRb regulates binding to E2F-1.
  findings: []
- id: PMID:16510145
  title: Effects of MdmX on Mdm2-mediated downregulation of pRB.
  findings: []
- id: PMID:16616919
  title: The arginine methyltransferase PRMT2 binds RB and regulates E2F function.
  findings: []
- id: PMID:16763564
  title: Roles for APIS and the 20S proteasome in adenovirus E1A-dependent transcription.
  findings: []
- id: PMID:16766265
  title: HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity.
  findings: []
- id: PMID:16964284
  title: Prohibitin, a protein downregulated by androgens, represses androgen receptor activity.
  findings: []
- id: PMID:17045206
  title: p53 family members in myogenic differentiation and rhabdomyosarcoma development.
  findings: []
- id: PMID:17274640
  title: A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis.
  findings: []
- id: PMID:17292836
  title: Structure of the oncoprotein gankyrin in complex with S6 ATPase of the 26S proteasome.
  findings: []
- id: PMID:17349581
  title: Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas.
  findings: []
- id: PMID:17380128
  title: Phosphorylation of pRB at Ser612 by Chk1/2 leads to a complex between pRB and E2F-1 after DNA damage.
  findings: []
- id: PMID:17540172
  title: L3MBTL1, a histone-methylation-dependent chromatin lock.
  findings: []
- id: PMID:17620057
  title: Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1.
  findings: []
- id: PMID:18391203
  title: EBV-encoded EBNA-6 binds and targets MRS18-2 to the nucleus, resulting in the disruption of pRb-E2F1 complexes.
  findings: []
- id: PMID:1870208
  title: Purification and characterization of human papillomavirus type 16 E7 protein with preferential binding capacity to the underphosphorylated form of retinoblastoma gene product.
  findings: []
- id: PMID:19017275
  title: Shigella flexneri type III secretion system effectors OspB and OspF target the nucleus to downregulate the host inflammatory response via interactions with retinoblastoma protein.
  findings: []
- id: PMID:19149898
  title: The chromatin remodelling factor BRG1 is a novel binding partner of the tumor suppressor p16INK4a.
  findings: []
- id: PMID:19223331
  title: HMGB1 and HMGB2 proteins up-regulate cellular expression of human topoisomerase IIalpha.
  findings: []
- id: PMID:19249677
  title: Proapoptotic function of the retinoblastoma tumor suppressor protein.
  findings: []
- id: PMID:19417128
  title: Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice.
  findings: []
- id: PMID:19513100
  title: Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis.
  findings: []
- id: PMID:19651603
  title: Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein.
  findings: []
- id: PMID:20088881
  title: Targeting mechanism of the retinoblastoma tumor suppressor by a prototypical viral oncoprotein. Structural modularity, intrinsic disorder and phosphorylation of human papillomavirus E7.
  findings: []
- id: PMID:20195357
  title: A comprehensive resource of interacting protein regions for refining human transcription factor networks.
  findings: []
- id: PMID:20551165
  title: Loss of pRB causes centromere dysfunction and chromosomal instability.
  findings: []
- id: PMID:20870719
  title: Methylation of the retinoblastoma tumor suppressor by SMYD2.
  findings: []
- id: PMID:20871633
  title: p38 phosphorylates Rb on Ser567 by a novel, cell cycle-independent mechanism that triggers Rb-Hdm2 interaction and apoptosis.
  findings: []
- id: PMID:20940255
  title: Acetylation of Rb by PCAF is required for nuclear localization and keratinocyte differentiation.
  findings: []
- id: PMID:21119616
  title: Interplay between lysine methylation and Cdk phosphorylation in growth control by the retinoblastoma protein.
  findings: []
- id: PMID:21139044
  title: Rb-Raf-1 interaction disruptor RRD-251 induces apoptosis in metastatic melanoma cells and synergizes with dacarbazine.
  findings: []
- id: PMID:2138977
  title: The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV40 large T antigen are common sites for mutations.
  findings: []
- id: PMID:2153075
  title: The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation.
  findings: []
- id: PMID:2162480
  title: Definition of the minimal simian virus 40 large T antigen- and adenovirus E1A-binding domain in the retinoblastoma gene product.
  findings: []
- id: PMID:2189724
  title: Two distinct and frequently mutated regions of retinoblastoma protein are required for binding to SV40 T antigen.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.
  findings: []
- id: PMID:21952639
  title: NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor.
  findings: []
- id: PMID:22157815
  title: The SNF2-like helicase HELLS mediates E2F3-dependent transcription and cellular transformation.
  findings: []
- id: PMID:22301153
  title: The coronavirus endoribonuclease Nsp15 interacts with retinoblastoma tumor suppressor protein.
  findings: []
- id: PMID:22366686
  title: Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells.
  findings: []
- id: PMID:22615382
  title: H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.
  findings: []
- id: PMID:22773103
  title: LEDGF (p75) promotes DNA-end resection and homologous recombination.
  findings: []
- id: PMID:22810586
  title: Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins.
  findings: []
- id: PMID:22898364
  title: Comparative analysis of virus-host interactomes with a mammalian high-throughput protein complementation assay based on Gaussia princeps luciferase.
  findings: []
- id: PMID:23472054
  title: The ING1a tumor suppressor regulates endocytosis to induce cellular senescence via the Rb-E2F pathway.
  findings: []
- id: PMID:23602568
  title: The protein interaction landscape of the human CMGC kinase group.
  findings: []
- id: PMID:23752268
  title: The functional interactome landscape of the human histone deacetylase family.
  findings: []
- id: PMID:23783631
  title: Modulation of allostery by protein intrinsic disorder.
  findings: []
- id: PMID:23859194
  title: Mitogen-activated protein kinase p38 and retinoblastoma protein signalling is required for DNA damage-mediated formation of senescence-associated heterochromatic foci in tumour cells.
  findings: []
- id: PMID:24027266
  title: MiR-26b, upregulated in Alzheimer's disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons.
  findings: []
- id: PMID:24823443
  title: HAUSP, a novel deubiquitinase for Rb - MDM2 the critical regulator.
  findings: []
- id: PMID:25100735
  title: Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells.
  findings: []
- id: PMID:25609649
  title: Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
  findings: []
- id: PMID:25814554
  title: Phospho-tyrosine dependent protein-protein interaction network.
  findings: []
- id: PMID:2730637
  title: Homology between a region of the human retinoblastoma gene and L1 family repetitive sequences.
  findings: []
- id: PMID:29521627
  title: A compartmentalized signaling network mediates crossover control in meiosis.
  findings: []
- id: PMID:29997244
  title: 'LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.'
  findings: []
- id: PMID:32707033
  title: Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.
  findings: []
- id: PMID:34591612
  title: A protein interaction landscape of breast cancer.
  findings: []
- id: PMID:34591642
  title: A protein network map of head and neck cancer reveals PIK3CA mutant drug sensitivity.
  findings: []
- id: PMID:35140242
  title: Human transcription factor protein interaction networks.
  findings: []
- id: PMID:3657987
  title: The retinoblastoma susceptibility gene encodes a nuclear phosphoprotein associated with DNA binding activity.
  findings: []
- id: PMID:39938803
  title: Structural and functional analysis of cancer-associated missense variants in the retinoblastoma protein pocket domain.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:7503932
  title: Dual retinoblastoma-binding proteins with properties related to a negative regulator of ras in yeast.
  findings: []
- id: PMID:7592647
  title: Association of human Pur alpha with the retinoblastoma protein, Rb, regulates binding to the single-stranded DNA Pur alpha recognition element.
  findings: []
- id: PMID:7651420
  title: Characterization of a novel 350-kilodalton nuclear phosphoprotein that is specifically involved in mitotic-phase progression.
  findings: []
- id: PMID:7664264
  title: The nuclear tyrosine kinase Rak associates with the retinoblastoma protein pRb.
  findings: []
- id: PMID:7791904
  title: Interaction between the retinoblastoma protein and the oncoprotein MDM2.
  findings: []
- id: PMID:7890747
  title: Binding of an interferon-inducible protein (p202) to the retinoblastoma protein.
  findings: []
- id: PMID:7923370
  title: The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest.
  findings: []
- id: PMID:8245034
  title: Structural and functional characterization of the HPV16 E7 protein expressed in bacteria.
  findings: []
- id: PMID:8288605
  title: Identification of discrete structural domains in the retinoblastoma protein. Amino-terminal domain is required for its oligomerization.
  findings: []
- id: PMID:8756624
  title: Cyclin-binding motifs are essential for the function of p21CIP1.
  findings: []
- id: PMID:9054499
  title: Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.
  findings: []
- id: PMID:9067421
  title: A DNA polymerase alpha accessory protein exhibits structural and functional similarities to SV40 large tumor antigen.
  findings: []
- id: PMID:9395244
  title: Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha.
  findings: []
- id: PMID:9448006
  title: The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein.
  findings: []
- id: PMID:9468139
  title: Retinoblastoma protein recruits histone deacetylase to repress transcription.
  findings: []
- id: PMID:9468140
  title: Retinoblastoma protein represses transcription by recruiting a histone deacetylase.
  findings: []
- id: PMID:9608663
  title: The rubella virus putative replicase interacts with the retinoblastoma tumor suppressor protein.
  findings: []
- id: PMID:9697699
  title: A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability.
  findings: []
- id: PMID:9858607
  title: Rb inhibits the intrinsic kinase activity of TATA-binding protein-associated factor TAFII250.
  findings: []
- id: PMID:9881977
  title: Direct suppression of Stat1 function during adenoviral infection.
  findings: []
- id: Reactome:R-HSA-113503
  title: PP2A mediated localization of RB1 protein in chromatin
  findings: []
- id: Reactome:R-HSA-187948
  title: Phosphorylation of proteins involved in the G1/S transition by Cyclin A:Cdk2
  findings: []
- id: Reactome:R-HSA-188191
  title: APC/C:Cdh1-mediated degradation of Skp2
  findings: []
- id: Reactome:R-HSA-188386
  title: Association of Rb with Cyclin E:Cdk2 complexes
  findings: []
- id: Reactome:R-HSA-188390
  title: Cyclin E:CDK2-mediated phosphorylation of RB1
  findings: []
- id: Reactome:R-HSA-2172666
  title: RB1 binds condensin II
  findings: []
- id: Reactome:R-HSA-69227
  title: Cyclin D:CDK4/6 phosphorylates RB1 and prevents RB1 binding to E2F1/2/3:DP1/2 complexes
  findings: []
- id: Reactome:R-HSA-9018017
  title: RB1 binds and inhibits E2F1/2/3:DP1/2 complexes
  findings: []
- id: Reactome:R-HSA-9659782
  title: Defective RB1 does not bind E2F1,(E2F2,E2F3)
  findings: []
- id: Reactome:R-HSA-9659820
  title: RB1 translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-9660615
  title: Defective RB1 does not translocate to the nucleus
  findings: []
- id: Reactome:R-HSA-9682712
  title: nsp15 binds RB1
  findings: []
- id: Reactome:R-HSA-9686969
  title: APC/C:Cdh1 polyubiquitinates SKP2
  findings: []
- id: Reactome:R-HSA-9686980
  title: RB1 recruits APC/C:Cdh1 complex to SKP2
  findings: []
- id: Reactome:R-HSA-9687377
  title: Defective RB1 does not form a complex with SKP2 and FZR1
  findings: []
- id: Reactome:R-HSA-9768288
  title: RB1 and TFAP2A bind CDH1 gene promoter
  findings: []
- id: Reactome:R-HSA-9851127
  title: NPM1-ALK-dependent repression of pRB phosphorylation
  findings: []
- id: Reactome:R-NUL-8985474
  title: Runx2 binds RB1
  findings: []
- id: Reactome:R-NUL-8985490
  title: Runx2:RB1 binds the BGLAP gene promoter
  findings: []
- id: file:human/RB1/RB1-deep-research-falcon.md
  title: RB1 deep research (falcon, 2024 reviews synthesis)
  findings: []
core_functions:
# Core function 1: Transcriptional corepressor at E2F-target promoters
# (canonical pocket-protein activity that enforces the G1/S restriction point)
- description: >-
    RB1 functions as the canonical transcriptional corepressor of the pocket protein family.
    Through its RB_A/RB_B pocket domains it binds activator E2F transcription factors
    (E2F1/2/3) on the promoters of S-phase genes, masks their transactivation domains and
    recruits chromatin-modifying corepressors (HDAC1, SUV39H1, BRG1/SMARCA4, polycomb and
    DNA methyltransferase activities) to durably silence the E2F transcriptional program in
    G0/G1 cells. This activity defines the G1 restriction point and is the most highly
    conserved evolved function of pocket proteins. RB1 is held in this active corepressor
    state when hypo- or mono-phosphorylated, and is sequentially inactivated by Cyclin-CDK
    complexes (Cyclin D-CDK4/6, Cyclin E-CDK2) that hyperphosphorylate ~16 Ser/Thr sites
    (e.g. T373, S608, S780, S807/S811, T826), releasing E2F to drive S-phase entry.
  molecular_function:
    id: GO:0003714
    label: transcription corepressor activity
  directly_involved_in:
  - id: GO:2000134
    label: negative regulation of G1/S transition of mitotic cell cycle
  - id: GO:0045892
    label: negative regulation of DNA-templated transcription
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0000785
    label: chromatin
  in_complex:
    id: GO:0035189
    label: Rb-E2F complex
  supported_by:
  - reference_id: PMID:7923370
    supporting_text: "The retinoblastoma tumor suppressor protein (RB) binds several cellular proteins involved in cell cycle progression."
  - reference_id: PMID:7923370
    supporting_text: "BRG1 contains an RB-binding motif found in viral oncoproteins and bound to the A/B pocket and the hypophosphorylated form of RB."
  - reference_id: file:human/RB1/RB1-deep-research-falcon.md
    supporting_text: "pRb's primary function is to enforce the G1 restriction point by binding and repressing activator E2Fs (classically E2F1/2/3) and thereby suppressing transcriptional programs required for DNA replication and S-phase entry"
  - reference_id: file:human/RB1/RB1-deep-research-falcon.md
    supporting_text: "RB can repress E2F-dependent transcription both by masking E2F transactivation domains and by recruiting chromatin modifiers"
  - reference_id: file:human/RB1/RB1-deep-research-falcon.md
    supporting_text: "RB-mediated repression is supported by recruitment of chromatin modifiers, including HDACs, DNA methyltransferases, and SUV39H1"
  - reference_id: file:human/RB1/RB1-deep-research-falcon.md
    supporting_text: "RB activity is classically regulated by cyclin-CDK phosphorylation, which weakens RB's repression of E2F and allows cell-cycle progression"