Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005654 nucleoplasm	IBA GO_REF:0000033	ACCEPT	Summary: PALB2 functions in the nucleoplasm, where it assembles the BRCA1-PALB2-BRCA2 HR complex. Well supported and at an appropriate level of specificity. Reason: PALB2 is a nuclear protein that acts in the nucleoplasm/on chromatin during HR; the phylogenetically-inferred location is consistent with experimental localization data. Supporting Evidence: PMID:16793542 PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions.
GO:0000724 double-strand break repair via homologous recombination	IBA GO_REF:0000033	ACCEPT	Summary: HR repair of DNA double-strand breaks is the central, well-established biological process for PALB2. Accept as a core function. Reason: Extensive experimental evidence establishes PALB2 as essential for HR; the IBA annotation is at the correct level of specificity. Supporting Evidence: PMID:19369211 PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex.
GO:0003677 DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: PALB2 has genuine, experimentally demonstrated DNA-binding activity through an N-terminal DNA-binding domain, with preference D-loop > dsDNA > ssDNA. Reason: DNA binding is directly supported by in vitro EMSA experiments with purified PALB2; the phylogenetic inference is consistent with the biochemistry. Supporting Evidence: PMID:20871616 Full length PALB2 bound all three species of DNA with the following preference: D-loop > dsDNA > ssDNA
GO:0000724 double-strand break repair via homologous recombination	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO mapping (IPR042417, PALB2 family) to HR repair. Consistent with the experimentally-established core function. Reason: The IEA mapping from the PALB2-specific InterPro family to HR is accurate and redundant with strong experimental evidence.
GO:0003677 DNA binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO mapping to DNA binding, consistent with experimentally demonstrated DNA-binding activity of PALB2. Reason: Accurate electronic mapping corroborated by experimental DNA-binding data.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Nucleus localization from UniProt subcellular-location mapping. Correct but less specific than nucleoplasm. Reason: PALB2 is a nuclear protein; the broad IEA location is accurate, with more specific nucleoplasm annotations also present.
GO:0005515 protein binding	IPI PMID:17420451 Analysis of PALB2/FANCN-associated breast cancer families.	MODIFY	Summary: IntAct interaction with BRCA2 (P51587). "Protein binding" is uninformative; the biologically meaningful activity is PALB2 acting as the molecular adaptor that bridges BRCA1 and BRCA2 for HR. Reason: Per curation guidelines the generic GO:0005515 term should be replaced with a specific molecular function. PALB2's BRCA2 interaction underlies its molecular adaptor/scaffold role coupling BRCA1 to BRCA2. Proposed replacements: protein-macromolecule adaptor activity
GO:0005515 protein binding	IPI PMID:19369211 PALB2 is an integral component of the BRCA complex required ...	MODIFY	Summary: Direct interaction with BRCA1 (P38398) via the coiled-coil domain; PALB2 is the molecular adaptor forming the BRCA1-PALB2-BRCA2 complex. Replace uninformative "protein binding" with protein-macromolecule adaptor activity. Reason: This is the defining BRCA1-bridging interaction of PALB2; molecular adaptor activity captures the function far better than generic protein binding. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19369211 PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex.
GO:0005515 protein binding	IPI PMID:19609323 Structural basis for recruitment of BRCA2 by PALB2.	MODIFY	Summary: Crystal structure of the PALB2 WD40 β-propeller bound to a BRCA2 peptide. The interaction underlies PALB2's adaptor/scaffold role recruiting BRCA2 to nuclear foci. Reason: Structurally-defined BRCA2-binding interaction; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19609323 Localization of BRCA2 to nuclear foci requires its association with the partner and localizer of BRCA2 (PALB2)
GO:0005515 protein binding	IPI PMID:20871616 Enhancement of RAD51 recombinase activity by the tumor suppr...	MARK AS OVER ANNOTATED	Summary: IntAct interactions with RAD51 (Q06609) and RAD51AP1. PALB2 directly binds RAD51 and stimulates its recombinase (D-loop) activity; "protein binding" is uninformative and the functional role is captured in core_functions. Reason: A real, functionally important interaction, but the generic term adds no information; the meaningful activity (DNA binding and RAD51 D-loop stimulation) is annotated separately and summarized in core_functions. Supporting Evidence: PMID:20871616 PALB2 binds DNA and physically interacts with RAD51.
GO:0005515 protein binding	IPI PMID:22193777 ChAM, a novel motif that mediates PALB2 intrinsic chromatin ...	MARK AS OVER ANNOTATED	Summary: Interactions detected in the ChAM/chromatin-binding study (with BRCA1, BRCA2 and RAD51 co-complex members). Uninformative generic term. Reason: These co-complex interactions reflect the BRCA complex/chromatin association already captured by more specific annotations; protein binding itself is uninformative.
GO:0005515 protein binding	IPI PMID:22244764 Structural basis for molecular interactions involving MRG do...	MARK AS OVER ANNOTATED	Summary: Structural study of MRG domains; interaction with MORF4L1/MRG15 (Q9UBU8-2). Peripheral chromatin-targeting interaction annotated with an uninformative term. Reason: MORF4L1 binding relates to chromatin targeting, a secondary/supporting role; protein binding is uninformative as a molecular function.
GO:0005515 protein binding	IPI PMID:22293751 APRIN is a cell cycle specific BRCA2-interacting protein req...	MARK AS OVER ANNOTATED	Summary: Interaction with BRCA2 (P51587) detected in a study of the BRCA2-interacting protein APRIN/PDS5B. Incidental co-complex detection; uninformative term. Reason: The BRCA2 co-complex detection here is incidental to the paper's focus; the informative PALB2-BRCA2 adaptor function is captured elsewhere.
GO:0005515 protein binding	IPI PMID:24141787 Breast cancer-associated missense mutants of the PALB2 WD40 ...	MARK AS OVER ANNOTATED	Summary: The PALB2 WD40 domain directly binds RAD51C, RAD51, BRCA2 and XRCC3, scaffolding an HR complex. Real, mechanistically important interactions but annotated with an uninformative term. Reason: The scaffolding role is captured by protein-macromolecule adaptor activity in core_functions; the generic protein binding term adds no information. Supporting Evidence: PMID:24141787 the PALB2 WD40 domain may scaffold the RAD51C, RAD51, and BRCA2 HR proteins into a complex
GO:0005515 protein binding	IPI PMID:24485656 Breast cancer proteins PALB2 and BRCA2 stimulate polymerase ...	MARK AS OVER ANNOTATED	Summary: Direct interaction with DNA polymerase eta (POLH, Q9Y253); with BRCA2, PALB2 stimulates POLH-mediated DNA synthesis at blocked forks. Uninformative generic term. Reason: A genuine but specialized replication-associated role; protein binding is uninformative and the function is described in core_functions/notes. Supporting Evidence: PMID:24485656 PALB2 and BRCA2 interact with Polη and are required to sustain the recruitment of Polη at blocked replication forks.
GO:0005515 protein binding	IPI PMID:25960410 Structural Basis for Multi-specificity of MRG Domains.	MARK AS OVER ANNOTATED	Summary: Structural study of MRG domain multi-specificity; interaction with MORF4L1/MRG15 (Q9UBU8-2). Peripheral chromatin-targeting interaction with uninformative term. Reason: Same as other MORF4L1 interactions; protein binding is uninformative.
GO:0005515 protein binding	IPI PMID:28319063 Compromised BRCA1-PALB2 interaction is associated with breas...	MODIFY	Summary: Direct interaction with BRCA1 (P38398) via the coiled-coil; the L35P variant abrogates it, linking loss of the PALB2-BRCA1 bridge to breast-cancer risk. Reason: Defining BRCA1-bridging interaction; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:28319063 The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: High-throughput interactome (protein communities/disease networks); interaction with MORF4L1 (Q9UBU8-2). Uninformative generic term from a large-scale screen. Reason: Large-scale interactome hit; protein binding is uninformative as a molecular function.
GO:0005515 protein binding	IPI PMID:29656893 DNA Repair Network Analysis Reveals Shieldin as a Key Regula...	MARK AS OVER ANNOTATED	Summary: DNA-repair network analysis; interaction with BRCA1 (P38398). Uninformative generic term from a network study. Reason: The functionally meaningful BRCA1 bridge is already captured by MODIFY of the dedicated BRCA1-interaction rows; this network-derived generic annotation is uninformative.
GO:0005515 protein binding	IPI PMID:30410870 Two Missense Variants Detected in Breast Cancer Probands Pre...	MODIFY	Summary: Interaction with BRCA2 (P51587); the paper characterizes BRCA2 missense variants that prevent BRCA2-PALB2 binding. Supports the adaptor/scaffold role. Reason: BRCA2-binding interaction central to the PALB2 adaptor function; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Binary interactome (HuRI) interaction with KEAP1 (Q14145). Reflects PALB2's secondary role in the KEAP1-NRF2 oxidative-stress pathway, not its HR-scaffold core function. Reason: A real but HR-independent interaction annotated with an uninformative term; not a core molecular function of PALB2. The mechanistic basis of this secondary role is established by PMID:22331464 (KEAP1-NRF2 antioxidant response). Supporting Evidence: PMID:22331464 PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: BioPlex proteome-scale network; interactions include BRCA2 (P51587), RAD51 (Q06609) and KEAP1 (Q14145). Large-scale generic interaction annotation. Reason: High-throughput interactome data; protein binding is uninformative and the meaningful interactions are captured elsewhere.
GO:0005515 protein binding	IPI PMID:34591612 A protein interaction landscape of breast cancer.	MARK AS OVER ANNOTATED	Summary: Breast-cancer protein interaction landscape; interactions include BRCA2 (P51587) and KEAP1 (Q14145). Large-scale generic interaction annotation. Reason: High-throughput interactome data; protein binding is uninformative.
GO:0000724 double-strand break repair via homologous recombination	IDA PMID:28398198 Functional and mutational landscapes of BRCA1 for homology-d...	ACCEPT	Summary: ComplexPortal IDA for HR; the study shows the BRCA1-PALB2 interaction governs the choice between HR and single-strand annealing. Core function. Reason: Direct assay evidence for PALB2's role in HR-mediated repair. Supporting Evidence: PMID:28398198 the BRCA1-PALB2 interaction dictates the choice between HR and SSA
GO:0005634 nucleus	NAS PMID:19369211 PALB2 is an integral component of the BRCA complex required ...	ACCEPT	Summary: Nuclear localization (ComplexPortal NAS). Correct; PALB2 acts in the nucleus, accumulating with RAD51 at DNA-damage sites. Reason: Consistent with all experimental localization data for PALB2. Supporting Evidence: PMID:19369211 the focal concentration of PALB2 and RAD51 at DSBs
GO:1990391 DNA repair complex	IPI PMID:19369211 PALB2 is an integral component of the BRCA complex required ...	ACCEPT	Summary: PALB2 is part of the BRCA1-PALB2-BRCA2 DNA repair complex. Appropriately specific complex annotation. Reason: Directly supported; PALB2 is an integral component of the trimeric BRCA1-PALB2-BRCA2 HR complex. Supporting Evidence: PMID:19369211 serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence localizes PALB2 to the nucleoplasm. Consistent with its site of action. Reason: Direct immunofluorescence evidence for nucleoplasmic localization, the site where PALB2 assembles the HR complex.
GO:0016607 nuclear speck	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: HPA immunofluorescence also reports nuclear-speckle localization. Retained but not part of the core HR function, which occurs at damage foci/chromatin. Reason: A valid IDA localization, but nuclear speckles are not where PALB2's core HR scaffold activity is established; mark as non-core rather than removing.
GO:0003697 single-stranded DNA binding	IMP PMID:31017574 Novel RNA and DNA strand exchange activity of the PALB2 DNA ...	ACCEPT	Summary: PALB2 N-terminal DNA-binding domain binds ssDNA and supports strand exchange; mutating the DNA-binding site reduces RAD51 foci and halves HDR efficiency. Reason: Experimentally demonstrated ssDNA binding that is functionally required for efficient HDR. Supporting Evidence: PMID:31017574 We identified a major DNA-binding site of PALB2, mutations in which reduce RAD51 foci formation and the overall HDR efficiency in cells by 50%.
GO:0003677 DNA binding	EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr...	ACCEPT	Summary: The PALB2 DNA-binding domain binds DNA and supports strand exchange in vitro. Genuine molecular function. Reason: Direct experimental demonstration of DNA binding by the PALB2-DBD. Supporting Evidence: PMID:39584160 the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro
GO:0042803 protein homodimerization activity	EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr...	ACCEPT	Summary: PALB2 self-associates via a coiled-coil-mediated dimerization, stabilized by its intrinsically disordered regions. Experimentally demonstrated. Reason: Direct biophysical evidence for coiled-coil-mediated homodimerization, a property important for focal accumulation at DNA breaks. Supporting Evidence: PMID:39584160 Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction.
GO:0042803 protein homodimerization activity	IMP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr...	ACCEPT	Summary: Mutational evidence supporting PALB2 self-association/dimerization. Consistent with the EXP annotation from the same study. Reason: Corroborates the homodimerization activity; retained for consistency with the EXP annotation. Supporting Evidence: PMID:39584160 Coiled-coil mediated dimerization is stabilized by interaction between intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction.
GO:0003697 single-stranded DNA binding	EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr...	ACCEPT	Summary: ssDNA binding by the PALB2-DBD, which also drives its structural compaction and tetramerization. Consistent with the IMP ssDNA-binding annotation. Reason: Direct experimental evidence for ssDNA binding by PALB2. Supporting Evidence: PMID:39584160 Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization.
GO:0051289 protein homotetramerization	EXP PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr...	KEEP AS NON CORE	Summary: ssDNA binding promotes PALB2 tetramerization in vitro, proposed to underlie a strand-exchange mechanism. Genuine but specialized higher-order self-assembly. Reason: Experimentally supported oligomeric state, but a mechanistic detail of PALB2 self-assembly rather than a core molecular function on its own; retained as non-core. Supporting Evidence: PMID:39584160 Single-stranded (ss)DNA binding promotes additional structural compaction and protein tetramerization.
GO:0003677 DNA binding	IPI PMID:39584160 The strand exchange domain of tumor suppressor PALB2 is intr...	ACCEPT	Summary: DNA binding annotated via interaction with a DNA substrate (ChEBI:9160). Consistent with the other DNA-binding annotations for PALB2. Reason: Corroborates PALB2 DNA binding; retained for consistency with the EXP/IDA/IBA DNA-binding annotations. Supporting Evidence: PMID:39584160 the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange in vitro
GO:0005634 nucleus	EXP PMID:16793542 Control of BRCA2 cellular and clinical functions by a nuclea...	ACCEPT	Summary: Experimental nuclear localization from the founding PALB2 study. Correct. Reason: Direct experimental evidence of nuclear localization. Supporting Evidence: PMID:16793542 PALB2 colocalizes with BRCA2 in nuclear foci
GO:0005634 nucleus	EXP PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo...	ACCEPT	Summary: Experimental nuclear localization within the XPG-BRCA2-PALB2 HR complex study. Correct. Reason: Direct experimental localization evidence; PALB2 is chromatin-associated and forms damage-induced foci. Supporting Evidence: PMID:26833090 XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation
GO:0005634 nucleus	EXP PMID:28319063 Compromised BRCA1-PALB2 interaction is associated with breas...	ACCEPT	Summary: Experimental nuclear localization consistent with PALB2 focus formation at DNA damage sites. Correct. Reason: Direct experimental localization evidence; PALB2 forms ionizing radiation-induced nuclear foci. Supporting Evidence: PMID:28319063 wt PALB2 forms IRIF that largely co-localize with those of BRCA1
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9704408	ACCEPT	Summary: Reactome-asserted nucleoplasm location (HR pathway module). Consistent with PALB2's site of action. Reason: Correct location; PALB2 acts in the nucleoplasm during HR.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9704330	ACCEPT	Summary: Reactome-asserted nucleoplasm location (defective HR module). Consistent. Reason: Correct nucleoplasmic location.
GO:0005515 protein binding	IPI PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo...	MARK AS OVER ANNOTATED	Summary: Interactions within the ERCC5/XPG-BRCA2-PALB2-DSS1-RAD51 HR complex (withs include XPG, BRCA2, RAD51). Real complex membership, uninformative generic term. Reason: The specific complex membership is captured by the protein-containing-complex annotation from the same paper; protein binding itself is uninformative. Supporting Evidence: PMID:26833090 XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion reduces their chromatin binding and subsequent RAD51 foci formation.
GO:0032991 protein-containing complex	IDA PMID:26833090 Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologo...	MODIFY	Summary: PALB2 is a component of an HR complex (ERCC5/XPG, BRCA2, PALB2, DSS1, RAD51). "Protein-containing complex" is very generic; a DNA repair complex term is more informative. Reason: Replace the top-level generic complex term with the more specific DNA repair complex, matching the HR complex demonstrated here and the BRCA1-PALB2-BRCA2 complex. Proposed replacements: DNA repair complex Supporting Evidence: PMID:26833090 XPG directly interacts with BRCA2, RAD51, and PALB2
GO:0000724 double-strand break repair via homologous recombination	IMP PMID:26323318 NUCKS1 is a novel RAD51AP1 paralog important for homologous ...	ACCEPT	Summary: HR annotation from a study (NUCKS1/RAD51AP1) that used PALB2 depletion within its HR (gene-conversion) assays. HR is the well-established core process for PALB2. Reason: HR is unambiguously PALB2's core function; per guidelines an experimental annotation is not removed for lack of cached full text, and the assigned process is clearly correct and directly assayed here. Supporting Evidence: PMID:26323318 knockdown of PALB2 by one of two different siRNAs elicits a more dramatic effect on gene conversion frequency than depletion of either NUCKS1 or RAD51AP1
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5685838	ACCEPT	Summary: Reactome nucleoplasm location (HR/D-loop pathway). Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5686410	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5686440	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5686469	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5686483	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5693539	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5693584	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5693589	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5693593	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5693620	ACCEPT	Summary: Reactome nucleoplasm location for the "D-loop formation mediated by PALB2, BRCA2 and RAD51" reaction. Directly relevant and consistent. Reason: Correct nucleoplasmic location; this reaction is a canonical PALB2 HR step.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9701199	ACCEPT	Summary: Reactome nucleoplasm location (defective D-loop formation module). Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9709601	ACCEPT	Summary: Reactome nucleoplasm location. Consistent. Reason: Correct nucleoplasmic location.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9853389	ACCEPT	Summary: Reactome nucleoplasm location (FIGNL1 binds RAD51 module). Consistent. Reason: Correct nucleoplasmic location.
GO:0000724 double-strand break repair via homologous recombination	IDA PMID:19369211 PALB2 is an integral component of the BRCA complex required ...	ACCEPT	Summary: Direct assay evidence that disrupting the BRCA1-PALB2 interaction causes defective HR. Core function. Reason: Direct experimental support for PALB2's essential role in HR repair. Supporting Evidence: PMID:19369211 cells harboring mutations with abrogated BRCA1-PALB2 interaction resulted in defective homologous recombination (HR) repair
GO:0000724 double-strand break repair via homologous recombination	IDA PMID:19423707 PALB2 regulates recombinational repair through chromatin ass...	ACCEPT	Summary: PALB2 chromatin association and oligomerization are required to anchor the BRCA2·RAD51 machinery at breaks for HR. Core function. Reason: Direct experimental evidence linking PALB2 focal accumulation to proficient HR. Supporting Evidence: PMID:19423707 PALB2 exists as homo-oligomers and that PALB2 oligomerization is essential for its focal accumulation at DNA breaks in vivo
GO:0003677 DNA binding	IDA PMID:20871616 Enhancement of RAD51 recombinase activity by the tumor suppr...	ACCEPT	Summary: Purified PALB2 binds ssDNA, dsDNA and D-loop (preference D-loop > dsDNA > ssDNA) via its N-terminal half. Direct biochemical evidence. Reason: Direct in vitro demonstration of PALB2 DNA-binding activity. Supporting Evidence: PMID:20871616 Full length PALB2 bound all three species of DNA with the following preference: D-loop > dsDNA > ssDNA
GO:0005515 protein binding	IPI PMID:19423707 PALB2 regulates recombinational repair through chromatin ass...	MODIFY	Summary: Interaction with BRCA2 (P51587); PALB2 refines its BRCA2-binding motif to the WD40 repeats and its chromatin association is a prerequisite for BRCA2 loading. Part of the adaptor/scaffold function. Reason: BRCA2-binding interaction central to PALB2's adaptor role; replace generic protein binding with protein-macromolecule adaptor activity. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:19423707 PALB2 localizes to chromatin and assembled as oligomers at the site of DNA damage, which then serves as an anchor for the loading of BRCA2 and RAD51
GO:0005515 protein binding	IPI PMID:20332121 MRG15 binds directly to PALB2 and stimulates homology-direct...	MARK AS OVER ANNOTATED	Summary: Direct interaction with MORF4L1/MRG15 (chromodomain protein), which promotes chromatin-associated homology-directed repair. Peripheral chromatin-targeting interaction with an uninformative term. Reason: A genuine chromatin-targeting interaction, but a supporting rather than core role; protein binding is uninformative as a molecular function. Supporting Evidence: PMID:20332121 PALB2 binds directly to a conserved chromodomain protein, MRG15
GO:0031491 nucleosome binding	IDA PMID:22193777 ChAM, a novel motif that mediates PALB2 intrinsic chromatin ...	NEW	Summary: PALB2's chromatin-association motif (ChAM) directly and intrinsically binds nucleosomes, mediating constitutive chromatin association that is distinct from the N-terminal DNA-binding regions. ChAM deletion reduces PALB2 and RAD51 accumulation at DNA-damage sites and confers mitomycin C hypersensitivity. Reason: A genuine, experimentally demonstrated molecular function (direct nucleosome binding by the ChAM motif) that is absent from GOA and was previously reflected only as uninformative "protein binding" (PMID:22193777 row above). Added as a NEW annotation but kept non-core: ChAM-mediated nucleosome/chromatin association is a targeting/anchoring activity that helps retain and position the BRCA1-PALB2-BRCA2 complex on chromatin, rather than the central molecular-adaptor function itself. Supporting Evidence: PMID:22193777 ChAM robustly binds to nucleosomes PMID:22193777 chromatin-association motif (ChAM), an evolutionarily conserved motif in PALB2, is necessary and sufficient to mediate its chromatin association in both unperturbed and damaged cells

Core Functions

Molecular adaptor/scaffold that physically bridges BRCA1 (via its N-terminal coiled-coil) and BRCA2 (via its C-terminal WD40 β-propeller), forming the BRCA1-PALB2-BRCA2 complex that localizes and stabilizes BRCA2 at damaged chromatin and promotes RAD51 loading for homologous recombination.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

double-strand break repair via homologous recombination

Cellular Locations:

nucleoplasm

In Complex:

DNA repair complex

Supporting Evidence:

PMID:19369211
PALB2, the partner and localizer of BRCA2, binds directly to BRCA1, and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2 complex.
PMID:39584160
The partner and localizer of BRCA2 (PALB2) is a scaffold protein linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR).

DNA-binding activity of the intrinsically disordered N-terminal domain (preference D-loop > dsDNA > ssDNA) that stimulates RAD51-mediated strand invasion and D-loop formation, promoting homologous recombination; the domain also has intrinsic strand-exchange activity and cooperates with RAD51AP1. The MF term is GO:0000217 DNA secondary structure binding rather than the bare GO:0003677 DNA binding, because the quoted evidence is a documented structural preference (D-loop over duplex over single-stranded) rather than sequence-independent DNA binding - the same reasoning applied to FANCI in this cohort.

Molecular Function:

DNA secondary structure binding

Directly Involved In:

double-strand break repair via homologous recombination

Cellular Locations:

nucleoplasm

Supporting Evidence:

PMID:20871616
Full length PALB2 bound all three species of DNA with the following preference: D-loop > dsDNA > ssDNA
PMID:31017574
We identified a major DNA-binding site of PALB2, mutations in which reduce RAD51 foci formation and the overall HDR efficiency in cells by 50%.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

PMID:16793542

Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.

PMID:17420451

Analysis of PALB2/FANCN-associated breast cancer families.

PMID:19369211

PALB2 is an integral component of the BRCA complex required for homologous recombination repair.

PMID:19423707

PALB2 regulates recombinational repair through chromatin association and oligomerization.

PMID:19609323

Structural basis for recruitment of BRCA2 by PALB2.

PMID:20332121

MRG15 binds directly to PALB2 and stimulates homology-directed repair of chromosomal breaks.

PMID:20871616

Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2.

PMID:22193777

ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates DNA repair.

PMID:22244764

Structural basis for molecular interactions involving MRG domains: implications in chromatin biology.

PMID:22293751

APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer.

PMID:22331464

PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function.

PMID:24141787

Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.

PMID:24485656

Breast cancer proteins PALB2 and BRCA2 stimulate polymerase η in recombination-associated DNA synthesis at blocked replication forks.

PMID:25960410

Structural Basis for Multi-specificity of MRG Domains.

PMID:26323318

NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability.

PMID:26833090

Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability.

PMID:28319063

Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.

PMID:28398198

Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:29656893

DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity.

PMID:30410870

Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2 Protein Interaction.

PMID:31017574

Novel RNA and DNA strand exchange activity of the PALB2 DNA binding domain and its critical role for DNA repair in cells.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34591612

A protein interaction landscape of breast cancer.

PMID:39584160

The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered and promotes oligomerization-dependent DNA compaction.

Reactome:R-HSA-5685838

CX3 complex binds D-loop structures

Reactome:R-HSA-5686410

BLM mediates dissolution of double Holliday junction

Reactome:R-HSA-5686440

MUS81:EME1,EME2 cleaves D-loop

Reactome:R-HSA-5686469

Resolution of D-loops cleaved by MUS81:EME1 or MUS81:EME2

Reactome:R-HSA-5686483

Resolution of Holliday junctions cleaved by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)

Reactome:R-HSA-5693539

Ligation of DNA and formation of Holliday structures following repair synthesis

Reactome:R-HSA-5693584

Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)

Reactome:R-HSA-5693589

D-loop dissociation and strand annealing

Reactome:R-HSA-5693593

D-loop extension by DNA polymerases

Reactome:R-HSA-5693620

D-loop formation mediated by PALB2, BRCA2 and RAD51

Reactome:R-HSA-9701199

Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function of BRCA1 in PALB2 binding

Reactome:R-HSA-9704330

Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function of PALB2 in BRCA1 binding

Reactome:R-HSA-9704408

Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function of PALB2 in binding to BRCA2/RAD51/RAD51C

Reactome:R-HSA-9709601

Defective recruitment of BRCA2 and RAD51 due to loss of BRCA2 function in PALB2 binding

Reactome:R-HSA-9853389

FIGNL1 binds RAD51

Suggested Experiments

Experiment: Generate separation-of-function PALB2 alleles that selectively disrupt DNA binding versus BRCA1 or BRCA2 binding, and assay HR efficiency, RAD51 foci formation, and PARP-inhibitor sensitivity to dissect the DNA-binding contribution from the adaptor/scaffold contribution.

Experiment: Structural and biophysical characterization (cryo-EM/SAXS) of the full BRCA1-PALB2-BRCA2 assembly on damaged chromatin to define the stoichiometry and geometry of the adaptor bridge.

Deep Research

Affinage

(PALB2-deep-research-affinage.md)

Affinage mechanistic annotation for PALB2 (human) Affinage Affinage (Claude Sonnet reading pass + Opus synthesis pass) 35 citations

Affinage mechanistic annotation for PALB2 (human)

Current model (mechanistic narrative)

PALB2 (Partner and Localizer of BRCA2) is the central scaffold of homologous recombination (HR) repair of DNA double-strand breaks, physically bridging BRCA1 and BRCA2 so that the recombinase machinery can be assembled at sites of damage [PMID:19268590, PMID:19584259]. Through its N-terminal coiled-coil it binds BRCA1 (residues L21/L24/L35) and through its C-terminus it binds BRCA2, thereby relaying BRCA1-mediated recruitment to BRCA2-RAD51 organization and strand invasion [PMID:17287723, PMID:19584259]; structurally the coiled-coil forms an antiparallel leucine-zipper that exists as a homodimer or as a BRCA1 heterodimer, and the switch from PALB2 homodimer to PALB2-BRCA1 heterodimer acts as the regulatory gate that activates HR [PMID:22941656, PMID:30289697]. PALB2 recruitment to breaks proceeds through an ubiquitin signaling cascade (MDC1, RNF8, RAP80, Abraxas upstream of BRCA1, and RNF168-generated ubiquitylated H2A read by BARD1-BRCA1), with the BRCA1-PALB2 heterodimer rather than the homodimer mediating RAD51 loading [PMID:23038782, PMID:28240985, PMID:34408138]. PALB2 carries intrinsic chromatin- and DNA-binding activities: a chromatin-association motif (ChAM) that engages the nucleosome acidic patch—an interaction antagonized by 53BP1 in BRCA1-deficient cells—and an N-terminal DNA-binding domain that stimulates RAD51 and possesses RAD51-independent strand-exchange activity [PMID:22193777, PMID:31017574, PMID:32041954]. Steady-state localization to actively transcribed genes occurs via MRG15 recognition of SETD2-deposited H3K36me3, protecting these regions during replication, and PALB2 is additionally recruited to stalled forks by phosphorylated RPA and sustains DNA polymerase η-dependent synthesis at blocked forks [PMID:28673974, PMID:25113031, PMID:24485656]. ATM/ATR-dependent phosphorylation of N-terminal S/Q sites is required for proper RAD51 foci formation and HR, and PALB2 also contributes to the G2/M checkpoint independently of CHK1/CHK2 [PMID:27113759, PMID:26420486, PMID:30337689]. Beyond DNA repair, PALB2 binds KEAP1 through a shared ETGE motif to promote NRF2-mediated antioxidant responses PMID:22331464. Patient-derived and systematic variant analyses establish that disruption of the BRCA1-PALB2 or BRCA2-PALB2 interactions, or destabilization of the WD40 domain, abolishes HR and confers sensitivity to platinum and PARP inhibitors, and mouse models disrupting these interactions produce Fanconi anemia-like and tumor-prone phenotypes [PMID:28319063, PMID:25016020, PMID:32732220, PMID:31636395, PMID:31757951].

Affinage mechanism profile (Affinage's own GO/Reactome grounding)

molecular_activity: GO:0060090 molecular adaptor activity, GO:0003677 DNA binding, GO:0140097 catalytic activity, acting on DNA, GO:0042393 histone binding, GO:0003723 RNA binding, GO:0098772 molecular function regulator activity
localization: GO:0005634 nucleus, GO:0000228 nuclear chromosome, GO:0005654 nucleoplasm
pathway (Reactome): R-HSA-73894 DNA Repair, R-HSA-69306 DNA Replication, R-HSA-1640170 Cell Cycle, R-HSA-4839726 Chromatin organization, R-HSA-8953897 Cellular responses to stimuli, R-HSA-74160 Gene expression (Transcription)
partners: BRCA2, BRCA1, MRG15, KEAP1, RNF168, RAD51C, USP22, RAD52
complexes: BRCA1-PALB2-BRCA2 HR complex, PALB2-MRG15 complex, PALB2-RAD52 complex

Dated findings (citation-anchored)

Year	Confidence	Finding	PMIDs	Journal
2007	High	PALB2 directly interacts with BRCA2 and this interaction is crucial for BRCA2 DNA damage response functions and tumor suppression activity. A truncated PALB2 protein caused by the c.1592delT frameshift mutation retained little BRCA2-binding capacity and was deficient in homologous recombination and crosslink repair.	PMID:17287723	Nature
2009	High	PALB2 physically links BRCA1 and BRCA2 in the DNA-damage response. BRCA1 associates with BRCA2 through PALB2; this interaction is abrogated in PALB2-deficient cells. BRCA1 promotes concentration of PALB2 and BRCA2 at DNA-damage sites, and the BRCA1-PALB2 interaction is required for homologous recombination repair.	PMID:19268590	Current biology : CB
2009	High	PALB2 independently interacts with BRCA1 through its N-terminus (via coiled-coil domain residues L21 and L24) and with BRCA2 through its C-terminus. PALB2 mediates the physical interaction of BRCA2 with a C-terminal fragment of BRCA1. BRCA1 recruits PALB2, which in turn organizes BRCA2 and RAD51. Both PALB2-BRCA1 and PALB2-BRCA2 interactions are required for resistance to mitomycin C and homologous recombination repair of DNA double-strand breaks.	PMID:19584259	Molecular cancer research : MCR
2010	High	PALB2 binds directly to MRG15, a chromodomain protein component of histone acetyltransferase-deacetylase complexes. MRG15 interacts with the entire BRCA complex (BRCA1, PALB2, BRCA2, RAD51). MRG15 deficiency, like PALB2 or BRCA2 deficiency, reduces homology-directed DNA repair efficiency and causes hypersensitivity to DNA interstrand crosslinking agents. Knockdown of MRG15 diminishes recruitment of PALB2, BRCA2, and RAD51 to DNA damage sites and reduces chromatin loading of PALB2 and BRCA2.	PMID:20332121, PMID:19553677	Journal of cell science
2009	High	MRG15 directly interacts with PALB2 through an evolutionarily conserved region. Loss of the PALB2-MRG15 interaction does not impair RAD51 foci formation or mitomycin C sensitivity but leads to hyper-recombination, specifically increased gene conversion rates and elevated sister chromatid exchange frequencies, suggesting MRG15 suppresses aberrant recombination via PALB2.	PMID:19553677	The Journal of biological chemistry
2012	High	PALB2 interacts directly with KEAP1, an oxidative stress sensor that normally binds and represses the NRF2 transcription factor. PALB2 shares a conserved ETGE-type KEAP1-binding motif with NRF2 and competes with NRF2 for KEAP1 binding. PALB2 promotes NRF2 nuclear accumulation and function, lowers cellular reactive oxygen species levels, and regulates the rate of NRF2 nuclear export following oxidative induction.	PMID:22331464	Molecular and cellular biology
2012	High	The N-terminal coiled-coil motif of PALB2 mediates its self-association (homodimerization), and monomeric PALB2 shows higher efficiency to bind DNA and promote RAD51 filament formation. Overexpression of the PALB2 coiled-coil domain severely affects RAD51 loading at DNA damage sites by competing with the PALB2-BRCA1 interaction. Upon DNA damage, a switch from PALB2-PALB2 homodimerization to PALB2-BRCA1 interaction activates homologous recombination.	PMID:22941656	Nucleic acids research
2012	High	The chromatin-association motif (ChAM), an evolutionarily conserved region of PALB2, is necessary and sufficient to mediate intrinsic chromatin binding of PALB2 in both unperturbed and damaged cells. ChAM is distinct from previously described DNA-binding regions. Deletion of ChAM decreases PALB2 and RAD51 accumulation at DNA damage sites and confers cellular hypersensitivity to mitomycin C.	PMID:22193777	EMBO reports
2012	High	MDC1 and RNF8 function upstream of BRCA1 in a pathway that directs BRCA1-dependent localization of PALB2 to DNA double-strand breaks. Bypassing BRCA1 by fusing PALB2 to BRCA1 BRCT repeats restores RAD51 foci formation and HR repair in PALB2-deficient cells even when PALB2 cannot bind BRCA1, demonstrating the critical role of PALB2 localization. The BRCA1-PALB2 heterodimer (not the PALB2-PALB2 homodimer) mediates these HR responses. PALB2 localization requires MDC1, RNF8, RAP80, and Abraxas upstream of BRCA1.	PMID:23038782	Journal of cell science
2014	High	Phosphorylated RPA (phosphorylated by Cdk2 and ATR during replication fork stalling) recruits PALB2 to stalled replication forks. RPA phosphorylation increased localization of PALB2 and BRCA2 to RPA-bound nuclear foci during replication stress, and phosphorylated RPA stimulated recruitment of PALB2 to single-stranded DNA in a cell-free system. Loss of PALB2 or expression of phosphorylation-defective RPA2 led to significant DNA damage after replication stress, exacerbated by PARP inhibitors.	PMID:25113031	The Journal of cell biology
2014	High	PALB2 and BRCA2 interact with DNA polymerase η (Polη) and colocalize with Polη at stalled or collapsed replication forks after hydroxyurea treatment. PALB2 and BRCA2 are required to sustain the recruitment of Polη at blocked replication forks and stimulate Polη-dependent DNA synthesis on D-loop substrates, implicating PALB2 in the initiation of recombination-associated DNA synthesis.	PMID:24485656	Cell reports
2014	Medium	PALB2 recruitment to DNA double-strand breaks is via a ubiquitin-dependent signaling pathway involving RAP80, Abraxas, and BRCA1. PALB2 also interacts with RAD51C and DNA polymerase η, forming a network of tumor suppressors required for homologous recombination.	PMID:24998779	Biochimica et biophysica acta
2016	High	PALB2 is phosphorylated at three N-terminal S/Q sites by ATM and ATR kinases in response to ionizing radiation and hydroxyurea. A phospho-deficient PALB2 mutant is unable to support proper RAD51 foci formation and is less potent in homology-directed repair, whereas a phospho-mimicking PALB2 supports RAD51 foci formation. The PALB2-dependent checkpoint response is unaffected by phospho-deficient PALB2, revealing a separation of PALB2 functions.	PMID:27113759	EMBO reports
2015	High	ATM phosphorylates PALB2 at Ser-157 and Ser-376 in response to ionizing radiation. Full phosphorylation also requires BRCA1, highlighting the importance of the BRCA1-PALB2 interaction in orchestrating DNA damage responses. Dysregulated PALB2 phosphorylation results in sustained activation of DNA damage responses.	PMID:26420486	The Journal of biological chemistry
2017	High	RNF168 contains a PALB2-interacting domain (PID) that directly binds the WD40 domain of PALB2. PALB2 indirectly recognizes H2A ubiquitylation by physically associating with ubiquitin-bound RNF168. This RNF168-PALB2 interaction facilitates assembly of PALB2-containing HR complexes at DSBs in S/G2 cells, coupling PALB2-dependent homologous recombination to H2A ubiquitylation.	PMID:28240985	eLife
2017	High	The PALB2-BRCA1 interaction (via PALB2 N-terminal coiled-coil domain residue L35P in patients) is required for breast cancer suppression. The L35P variant abrogates the PALB2-BRCA1 interaction and completely disables PALB2's ability to promote HR and confer resistance to platinum salts and PARP inhibitors. Multiple additional germline variants in the PALB2 N-terminal BRCA1-binding domain affect HR function to varying degrees.	PMID:28319063	Oncogene
2017	High	PALB2 associates with active genes through MRG15, which recognizes histone H3 trimethylated at lysine 36 (H3K36me3) via the SETD2 methyltransferase. PALB2-MRG15 interaction mutations confer elevated sensitivity to the topoisomerase inhibitor camptothecin and increased DNA stress in gene bodies during replication. The steady-state presence of PALB2 at active genes via the SETD2/H3K36me3/MRG15 axis protects these regions during DNA replication.	PMID:28673974	Proceedings of the National Academy of Sciences of the United States of America
2018	High	PALB2 connects BRCA1 and BRCA2 in the G2/M DNA damage checkpoint response. The BRCA1-PALB2 interaction contributes to checkpoint activation while the PALB2-BRCA2 complex is more critical for checkpoint maintenance. PALB2 checkpoint function is independent of CHK1 and CHK2 phosphorylation. Cells with disengaged BRCA1-PALB2 interaction show greatly increased chromosomal abnormalities after ionizing radiation due to combined defects in HR and checkpoint control.	PMID:30337689	Oncogene
2018	High	The PALB2 N-terminal coiled-coil domain forms an antiparallel coiled-coil leucine zipper homodimer as determined by solution NMR spectroscopy. PALB2cc also forms heterodimers with the BRCA1 coiled-coil segment. Mutation of Leu24 in PALB2cc significantly reduces homodimer stability but has a more modest effect on PALB2cc/BRCA1cc heterodimer stability. Leu24 mutation leads to genomic instability and reduced cell viability after DNA double-strand break-inducing agents.	PMID:30289697	Biochemistry
2019	High	PALB2 possesses a major DNA-binding site in its N-terminal DNA-binding domain (N-DBD). Mutations in this site reduce RAD51 foci formation and overall HDR efficiency in cells by ~50%. The N-DBD stimulates RAD51 recombinase function and also possesses strand exchange activity without RAD51, including the ability to use RNA substrates and stimulate inverse strand exchange.	PMID:31017574	eLife
2019	Medium	USP22, a deubiquitinase, directly interacts with PALB2 through the C-terminal WD40 domain of PALB2. This interaction stimulates USP22 catalytic deubiquitinase activity in vitro. USP22 is required for BRCA2, PALB2, and RAD51 recruitment to DNA double-strand breaks, partly through USP22 stabilizing BRCA2 and PALB2 protein levels.	PMID:31685642	Molecular cancer research : MCR
2020	High	In BRCA1-null/53BP1-depleted cells, PALB2 recruitment to resected DSBs is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region. In 53BP1-expressing cells, this acidic patch is occupied by 53BP1's ubiquitin-directed recruitment (UDR) domain, blocking PALB2 access. Loss of 53BP1 in BRCA1-deficient cells restores PALB2 accrual at DSBs in a PALB2- and BRCA2-dependent manner, partially restoring HR.	PMID:32041954	Nature communications
2021	High	RNF168-generated mono-ubiquitinated H2A (mUb-H2A) recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the coiled-coil domain-mediated BRCA1-PALB2 interaction. Epistatic analysis in mice harboring a Brca1CC mutation (blocking Brca1-Palb2 interaction) combined with Rnf168 loss disrupted development and reduced Palb2-Rad51 localization.	PMID:34408138	Nature communications
2021	Medium	BRCA1 and RNAi factors promote sdRNA (single-stranded DNA-damage-associated small RNA)-mediated DNA repair at transcriptional termination pause sites via the PALB2-RAD52 complex. sdRNAs promote DNA repair driven by PALB2-RAD52 at R-loop-rich sites with single-stranded DNA breaks, operating in both quiescent (G0) and proliferating cells.	PMID:33536619	Nature
2022	Medium	Disruption of the BRCA1-PALB2 interaction causes persistent high levels of DNA damage in HCC cells, leading to activation of the cGAS-STING signaling pathway in both malignant hepatocytes and M1 macrophages. The activated cGAS-STING pathway induces PD-L1 expression via STING-IRF3-STAT1, causing immunosuppression, while also recruiting T lymphocytes through the STING-IRF3 pathway.	PMID:35006619	Hepatology (Baltimore, Md.)
2014	High	Disruption of the BRCA1-PALB2 interaction in mice (hypomorphic Palb2 allele expressing BRCA1-binding-deficient PALB2) causes Fanconi anemia-like phenotype including hypersensitivity and chromosomal breakage with mitomycin C, reduced male fertility due to impaired meiosis, increased germ cell apoptosis, and significant defect in sex chromosome synapsis in meiocytes.	PMID:25016020	The Journal of biological chemistry
2016	High	The BRCA2-PALB2 interaction (mediated by the N-terminal region of BRCA2) is essential for maintaining genomic integrity. Knock-in mice carrying Brca2G25R (a single amino acid change disrupting BRCA2-PALB2 interaction) show defects in body size, fertility, meiotic progression, genome stability, and increased tumor susceptibility. Severity increased with decreasing interaction, demonstrating that BRCA1-PALB2-BRCA2 complex formation and BRCA2's DNA-binding domain have overlapping roles in BRCA2 recruitment to DNA damage sites.	PMID:27490902	PLoS genetics
2013	High	The N-terminal segment of BRCA2 (PALB2-binding domain) and the DNA-binding domain (DBD) of BRCA2 play substantially overlapping roles in BRCA2 function. Loss of both domains (BRCA2ΔN+ΔDBD) phenocopies BRCA2-null cells, while single deletions show moderate phenotypes. Formation of the BRCA1-PALB2-BRCA2 complex and the DBD are both required for efficient BRCA2 recruitment to DNA damage sites.	PMID:24285729	Cancer research
2014	Medium	BRCA1 and PALB2 co-occupy chromatin at actively transcribed genes genome-wide and are required for transcriptional responsiveness to NF-κB and retinoic acid. PALB2 plays a role in transcriptional co-activation in breast epithelial cells.	PMID:24591564	The EMBO journal
2010	High	Homozygous deletion of Palb2 in mice causes embryonic lethality at E9.5 with defective mesoderm differentiation after gastrulation and increased p21 expression. Palb2-/- blastocysts show growth defect in vitro. The phenotype resembles Brca1 and Brca2 knockout mice, supporting the in vivo functional relationship of PALB2 with BRCA1 and BRCA2.	PMID:20484223	Human molecular genetics
2020	High	Ablation of the Brca1-Palb2 interaction in mice (Brca1L1363P knock-in) causes Fanconi anemia-like phenotypes: hypersensitivity to DNA-damaging agents, failure to recruit Rad51 to DSBs, growth retardation, hyperpigmentation, skeletal abnormalities, male/female infertility, macrocytosis, and death from bone marrow failure or lymphoblastic lymphoma/leukemia.	PMID:32732220	Cancer research
2022	High	Pentagalloylglucose (PGG) disrupts the PALB2-BRCA2 protein-protein interaction by occupying a binding groove in the WD40 domain of PALB2 (tips of the fourth and fifth blades). PGG reduces BRCA2 recruitment to DNA damage sites and inhibits RAD51 foci formation, suppressing homologous recombination repair, and sensitizes cancer cells to PARP inhibitors and radiotherapy.	PMID:35926819	Cancer letters
2019	High	Functional analysis of 84 PALB2 missense variants of uncertain significance identified four variants (L24S, L35P, I944N, L1070P) that disrupt PALB2-mediated homology-directed repair. L24S and L35P disrupt BRCA1-PALB2 protein complexes; I944N causes protein instability; both I944N and L1070P mislocalize PALB2 to the cytoplasm. All four variants confer sensitivity to cisplatin and PARP inhibitors and reduce RAD51 foci formation.	PMID:31636395	Genetics in medicine : official journal of the American College of Medical Genetics
2019	High	Functional analysis of 48 PALB2 VUS using cDNA-based HR rescue in Palb2 knockout mouse ES cells identified three VUS in the coiled-coil domain that abrogate BRCA1 interaction and several VUS in the WD40 domain that dramatically reduce protein stability.	PMID:31757951	Nature communications
2022	Medium	Loss of PALB2 in prostate cancer cell lines leads to decreased homologous recombination function (measured by loss of radiation-induced RAD51 foci and HR reporter assay) and significantly increased sensitivity to PARP inhibitors olaparib and rucaparib.	PMID:35768576	NPJ precision oncology

Citations

PMID:17287723
PMID:19268590
PMID:19553677
PMID:19584259
PMID:20332121
PMID:20484223
PMID:22193777
PMID:22331464
PMID:22941656
PMID:23038782
PMID:24285729
PMID:24485656
PMID:24591564
PMID:24998779
PMID:25016020
PMID:25113031
PMID:26420486
PMID:27113759
PMID:27490902
PMID:28240985
PMID:28319063
PMID:28673974
PMID:30289697
PMID:30337689
PMID:31017574
PMID:31636395
PMID:31685642
PMID:31757951
PMID:32041954
PMID:32732220
PMID:33536619
PMID:34408138
PMID:35006619
PMID:35768576
PMID:35926819

📚 Additional Documentation

Notes

(PALB2-notes.md)

PALB2 (Q86YC2) review notes

PALB2 = Partner And Localizer of BRCA2 / FANCN. Human, 1186 aa, chr16. Tumor suppressor;
biallelic loss = Fanconi anemia group N (FANCN); monoallelic = breast/pancreatic/ovarian
cancer predisposition.

Domain architecture (from UniProt Q86YC2)

N-terminal coiled-coil (res ~9-41): binds BRCA1; also mediates self-oligomerization.
N-terminal region 1-579: DNA-binding domain (preference D-loop > dsDNA > ssDNA).
RAD51 interaction region ~101-184 (mapped in PMID:20871616).
ChAM (chromatin-association motif, ~395-446): intrinsic chromatin/nucleosome binding.
C-terminal 7-bladed WD40 β-propeller (~853-1186): binds BRCA2 (pocket at WD4/WD5
crossover), and also RAD51C, RAD51, XRCC3; also required for POLH interaction.

Core biology (verified from cached publications)

Scaffold/adaptor: PALB2 physically links BRCA1 (coiled-coil) to BRCA2 (WD40), forming the
BRCA1-PALB2-BRCA2 complex required for HR. PMID:19369211 and PMID:19369211.
Localizes/stabilizes BRCA2. PMID:16793542.
WD40 domain binds BRCA2 (structure). PMID:19609323 and structure of "PALB2 carboxy-terminal β-propeller domain in complex with a BRCA2 peptide".
WD40 also directly binds RAD51C, RAD51, BRCA2, XRCC3; scaffolds an HR complex. PMID:24141787 and PMID:24141787.
Chromatin association + oligomerization anchor BRCA2·RAD51 at breaks. PMID:19423707 and PMID:19423707.
DNA binding: N-terminal half binds DNA, D-loop > dsDNA > ssDNA. PMID:20871616.
Stimulates RAD51 recombinase / D-loop formation, cooperates with RAD51AP1. PMID:20871616 and PMID:20871616.
N-DBD has intrinsic strand-exchange activity; DNA binding needed for RAD51 foci/HDR. PMID:31017574 and PMID:31017574.
Strand-exchange/DBD is intrinsically disordered; coiled-coil dimerization + ssDNA-driven tetramerization; scaffold linking BRCA1-BRCA2-RAD51. PMID:39584160 and PMID:39584160.
With BRCA2 stimulates POLH DNA synthesis at blocked forks. PMID:24485656.
Part of an ERCC5/XPG-BRCA2-PALB2-DSS1-RAD51 HR complex. PMID:26833090.
BRCA1-PALB2 interaction directs HR vs SSA choice. PMID:28398198 and PMID:28319063.
MRG15/MORF4L1 binds PALB2 (chromatin targeting). PMID:20332121.

Review decisions summary

Core molecular function best captured as molecular adaptor activity (GO:0060090):
PALB2 bridges BRCA1 and BRCA2 (and scaffolds RAD51C/RAD51/XRCC3) for HR. Uninformative
"protein binding" (GO:0005515) IPI rows to BRCA1/BRCA2 MODIFIED -> GO:0060090; the many
other IPI rows (RAD51, RAD51C, XRCC3, RAD51AP1, MORF4L1, POLH, KEAP1, XPG, high-throughput
interactome papers) MARKED_AS_OVER_ANNOTATED (real interactions but uninformative term;
informative role captured in core_functions).
Genuine DNA binding (GO:0003677), ssDNA binding (GO:0003697), homodimerization
(GO:0042803), homotetramerization (GO:0051289) accepted (experimental).
HR (GO:0000724) accepted across IBA/IEA/IDA/IMP. Nucleoplasm/nucleus accepted; nuclear
speck (HPA IDA) kept as non-core.
KEAP1 interaction (KEAP1-NRF2 oxidative-stress) is a secondary role, not the HR-scaffold
core function; over-annotated as protein binding.

📄 View Raw YAML

id: Q86YC2
gene_symbol: PALB2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PALB2 (Partner And Localizer of BRCA2; FANCN) is a nuclear scaffold/adaptor protein
  central to homologous recombination (HR) repair of DNA double-strand breaks and
  interstrand crosslinks. Its N-terminal coiled-coil binds BRCA1 and mediates
  self-oligomerization, while its C-terminal seven-bladed WD40 β-propeller binds BRCA2
  (and also RAD51C, RAD51 and XRCC3). By simultaneously engaging BRCA1 and BRCA2, PALB2
  physically bridges the two breast-cancer suppressors, forming the BRCA1-PALB2-BRCA2
  complex that localizes and stabilizes BRCA2 at damaged chromatin and thereby promotes
  loading of the RAD51 recombinase to initiate strand invasion. PALB2 additionally binds
  DNA directly through an intrinsically disordered N-terminal domain (preference D-loop >
  dsDNA > ssDNA), stimulates RAD51-mediated D-loop formation (cooperating with RAD51AP1),
  possesses intrinsic strand-exchange activity, and associates with chromatin/nucleosomes
  via its ChAM motif. With BRCA2 it also stimulates POLH-dependent DNA synthesis at blocked
  replication forks. PALB2 acts in the nucleoplasm and accumulates at DNA-damage foci.
  Biallelic loss-of-function causes Fanconi anemia complementation group N, whereas
  heterozygous truncating mutations confer strong predisposition to breast, pancreatic and
  ovarian cancer. A secondary, HR-independent role is its interaction with KEAP1 in the
  oxidative-stress (NRF2) response.
existing_annotations:
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: PALB2 functions in the nucleoplasm, where it assembles the BRCA1-PALB2-BRCA2
      HR complex. Well supported and at an appropriate level of specificity.
    action: ACCEPT
    reason: PALB2 is a nuclear protein that acts in the nucleoplasm/on chromatin during
      HR; the phylogenetically-inferred location is consistent with experimental
      localization data.
    supported_by:
    - reference_id: PMID:16793542
      supporting_text: PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization
        and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and
        enables its recombinational repair and checkpoint functions.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: HR repair of DNA double-strand breaks is the central, well-established
      biological process for PALB2. Accept as a core function.
    action: ACCEPT
    reason: Extensive experimental evidence establishes PALB2 as essential for HR; the
      IBA annotation is at the correct level of specificity.
    supported_by:
    - reference_id: PMID:19369211
      supporting_text: PALB2, the partner and localizer of BRCA2, binds directly to BRCA1,
        and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2
        complex.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: PALB2 has genuine, experimentally demonstrated DNA-binding activity through
      an N-terminal DNA-binding domain, with preference D-loop > dsDNA > ssDNA.
    action: ACCEPT
    reason: DNA binding is directly supported by in vitro EMSA experiments with purified
      PALB2; the phylogenetic inference is consistent with the biochemistry.
    supported_by:
    - reference_id: PMID:20871616
      supporting_text: 'Full length PALB2 bound all three species of DNA with the following
        preference: D-loop > dsDNA > ssDNA'
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO mapping (IPR042417, PALB2 family) to HR repair. Consistent with
      the experimentally-established core function.
    action: ACCEPT
    reason: The IEA mapping from the PALB2-specific InterPro family to HR is accurate and
      redundant with strong experimental evidence.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO mapping to DNA binding, consistent with experimentally demonstrated
      DNA-binding activity of PALB2.
    action: ACCEPT
    reason: Accurate electronic mapping corroborated by experimental DNA-binding data.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nucleus localization from UniProt subcellular-location mapping. Correct but
      less specific than nucleoplasm.
    action: ACCEPT
    reason: PALB2 is a nuclear protein; the broad IEA location is accurate, with more
      specific nucleoplasm annotations also present.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17420451
  qualifier: enables
  review:
    summary: IntAct interaction with BRCA2 (P51587). "Protein binding" is uninformative;
      the biologically meaningful activity is PALB2 acting as the molecular adaptor that
      bridges BRCA1 and BRCA2 for HR.
    action: MODIFY
    reason: Per curation guidelines the generic GO:0005515 term should be replaced with a
      specific molecular function. PALB2's BRCA2 interaction underlies its molecular
      adaptor/scaffold role coupling BRCA1 to BRCA2.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19369211
  qualifier: enables
  review:
    summary: Direct interaction with BRCA1 (P38398) via the coiled-coil domain; PALB2 is
      the molecular adaptor forming the BRCA1-PALB2-BRCA2 complex. Replace uninformative
      "protein binding" with protein-macromolecule adaptor activity.
    action: MODIFY
    reason: This is the defining BRCA1-bridging interaction of PALB2; molecular adaptor
      activity captures the function far better than generic protein binding.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:19369211
      supporting_text: PALB2, the partner and localizer of BRCA2, binds directly to BRCA1,
        and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2
        complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19609323
  qualifier: enables
  review:
    summary: Crystal structure of the PALB2 WD40 β-propeller bound to a BRCA2 peptide.
      The interaction underlies PALB2's adaptor/scaffold role recruiting BRCA2 to nuclear
      foci.
    action: MODIFY
    reason: Structurally-defined BRCA2-binding interaction; replace generic protein binding
      with protein-macromolecule adaptor activity.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:19609323
      supporting_text: Localization of BRCA2 to nuclear foci requires its association with
        the partner and localizer of BRCA2 (PALB2)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20871616
  qualifier: enables
  review:
    summary: IntAct interactions with RAD51 (Q06609) and RAD51AP1. PALB2 directly binds
      RAD51 and stimulates its recombinase (D-loop) activity; "protein binding" is
      uninformative and the functional role is captured in core_functions.
    action: MARK_AS_OVER_ANNOTATED
    reason: A real, functionally important interaction, but the generic term adds no
      information; the meaningful activity (DNA binding and RAD51 D-loop stimulation) is
      annotated separately and summarized in core_functions.
    supported_by:
    - reference_id: PMID:20871616
      supporting_text: PALB2 binds DNA and physically interacts with RAD51.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22193777
  qualifier: enables
  review:
    summary: Interactions detected in the ChAM/chromatin-binding study (with BRCA1, BRCA2
      and RAD51 co-complex members). Uninformative generic term.
    action: MARK_AS_OVER_ANNOTATED
    reason: These co-complex interactions reflect the BRCA complex/chromatin association
      already captured by more specific annotations; protein binding itself is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22244764
  qualifier: enables
  review:
    summary: Structural study of MRG domains; interaction with MORF4L1/MRG15 (Q9UBU8-2).
      Peripheral chromatin-targeting interaction annotated with an uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: MORF4L1 binding relates to chromatin targeting, a secondary/supporting role;
      protein binding is uninformative as a molecular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22293751
  qualifier: enables
  review:
    summary: Interaction with BRCA2 (P51587) detected in a study of the BRCA2-interacting
      protein APRIN/PDS5B. Incidental co-complex detection; uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The BRCA2 co-complex detection here is incidental to the paper's focus; the
      informative PALB2-BRCA2 adaptor function is captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24141787
  qualifier: enables
  review:
    summary: The PALB2 WD40 domain directly binds RAD51C, RAD51, BRCA2 and XRCC3, scaffolding
      an HR complex. Real, mechanistically important interactions but annotated with an
      uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The scaffolding role is captured by protein-macromolecule adaptor activity in core_functions;
      the generic protein binding term adds no information.
    supported_by:
    - reference_id: PMID:24141787
      supporting_text: the PALB2 WD40 domain may scaffold the RAD51C, RAD51, and BRCA2 HR
        proteins into a complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24485656
  qualifier: enables
  review:
    summary: Direct interaction with DNA polymerase eta (POLH, Q9Y253); with BRCA2, PALB2
      stimulates POLH-mediated DNA synthesis at blocked forks. Uninformative generic term.
    action: MARK_AS_OVER_ANNOTATED
    reason: A genuine but specialized replication-associated role; protein binding is
      uninformative and the function is described in core_functions/notes.
    supported_by:
    - reference_id: PMID:24485656
      supporting_text: PALB2 and BRCA2 interact with Polη and are required to sustain the
        recruitment of Polη at blocked replication forks.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25960410
  qualifier: enables
  review:
    summary: Structural study of MRG domain multi-specificity; interaction with MORF4L1/MRG15
      (Q9UBU8-2). Peripheral chromatin-targeting interaction with uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Same as other MORF4L1 interactions; protein binding is uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28319063
  qualifier: enables
  review:
    summary: Direct interaction with BRCA1 (P38398) via the coiled-coil; the L35P variant
      abrogates it, linking loss of the PALB2-BRCA1 bridge to breast-cancer risk.
    action: MODIFY
    reason: Defining BRCA1-bridging interaction; replace generic protein binding with
      protein-macromolecule adaptor activity.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:28319063
      supporting_text: The two BRCA proteins are linked by a third tumor suppressor, PALB2,
        in the HR pathway.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome (protein communities/disease networks); interaction
      with MORF4L1 (Q9UBU8-2). Uninformative generic term from a large-scale screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: Large-scale interactome hit; protein binding is uninformative as a molecular
      function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29656893
  qualifier: enables
  review:
    summary: DNA-repair network analysis; interaction with BRCA1 (P38398). Uninformative
      generic term from a network study.
    action: MARK_AS_OVER_ANNOTATED
    reason: The functionally meaningful BRCA1 bridge is already captured by MODIFY of the
      dedicated BRCA1-interaction rows; this network-derived generic annotation is
      uninformative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30410870
  qualifier: enables
  review:
    summary: Interaction with BRCA2 (P51587); the paper characterizes BRCA2 missense
      variants that prevent BRCA2-PALB2 binding. Supports the adaptor/scaffold role.
    action: MODIFY
    reason: BRCA2-binding interaction central to the PALB2 adaptor function; replace
      generic protein binding with protein-macromolecule adaptor activity.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome (HuRI) interaction with KEAP1 (Q14145). Reflects PALB2's
      secondary role in the KEAP1-NRF2 oxidative-stress pathway, not its HR-scaffold core
      function.
    action: MARK_AS_OVER_ANNOTATED
    reason: A real but HR-independent interaction annotated with an uninformative term;
      not a core molecular function of PALB2. The mechanistic basis of this secondary role
      is established by PMID:22331464 (KEAP1-NRF2 antioxidant response).
    supported_by:
    - reference_id: PMID:22331464
      supporting_text: PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding
        motif and can effectively compete with NRF2 for KEAP1 binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex proteome-scale network; interactions include BRCA2 (P51587), RAD51
      (Q06609) and KEAP1 (Q14145). Large-scale generic interaction annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data; protein binding is uninformative and the
      meaningful interactions are captured elsewhere.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:34591612
  qualifier: enables
  review:
    summary: Breast-cancer protein interaction landscape; interactions include BRCA2
      (P51587) and KEAP1 (Q14145). Large-scale generic interaction annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome data; protein binding is uninformative.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IDA
  original_reference_id: PMID:28398198
  qualifier: involved_in
  review:
    summary: ComplexPortal IDA for HR; the study shows the BRCA1-PALB2 interaction governs
      the choice between HR and single-strand annealing. Core function.
    action: ACCEPT
    reason: Direct assay evidence for PALB2's role in HR-mediated repair.
    supported_by:
    - reference_id: PMID:28398198
      supporting_text: the BRCA1-PALB2 interaction dictates the choice between HR and SSA
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:19369211
  qualifier: located_in
  review:
    summary: Nuclear localization (ComplexPortal NAS). Correct; PALB2 acts in the nucleus,
      accumulating with RAD51 at DNA-damage sites.
    action: ACCEPT
    reason: Consistent with all experimental localization data for PALB2.
    supported_by:
    - reference_id: PMID:19369211
      supporting_text: the focal concentration of PALB2 and RAD51 at DSBs
- term:
    id: GO:1990391
    label: DNA repair complex
  evidence_type: IPI
  original_reference_id: PMID:19369211
  qualifier: part_of
  review:
    summary: PALB2 is part of the BRCA1-PALB2-BRCA2 DNA repair complex. Appropriately
      specific complex annotation.
    action: ACCEPT
    reason: Directly supported; PALB2 is an integral component of the trimeric BRCA1-PALB2-BRCA2
      HR complex.
    supported_by:
    - reference_id: PMID:19369211
      supporting_text: serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2
        complex
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence localizes PALB2 to the nucleoplasm. Consistent with
      its site of action.
    action: ACCEPT
    reason: Direct immunofluorescence evidence for nucleoplasmic localization, the site
      where PALB2 assembles the HR complex.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence also reports nuclear-speckle localization. Retained
      but not part of the core HR function, which occurs at damage foci/chromatin.
    action: KEEP_AS_NON_CORE
    reason: A valid IDA localization, but nuclear speckles are not where PALB2's core HR
      scaffold activity is established; mark as non-core rather than removing.
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: IMP
  original_reference_id: PMID:31017574
  qualifier: enables
  review:
    summary: PALB2 N-terminal DNA-binding domain binds ssDNA and supports strand exchange;
      mutating the DNA-binding site reduces RAD51 foci and halves HDR efficiency.
    action: ACCEPT
    reason: Experimentally demonstrated ssDNA binding that is functionally required for
      efficient HDR.
    supported_by:
    - reference_id: PMID:31017574
      supporting_text: We identified a major DNA-binding site of PALB2, mutations in which
        reduce RAD51 foci formation and the overall HDR efficiency in cells by 50%.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: EXP
  original_reference_id: PMID:39584160
  qualifier: enables
  review:
    summary: The PALB2 DNA-binding domain binds DNA and supports strand exchange in vitro.
      Genuine molecular function.
    action: ACCEPT
    reason: Direct experimental demonstration of DNA binding by the PALB2-DBD.
    supported_by:
    - reference_id: PMID:39584160
      supporting_text: the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange
        in vitro
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: EXP
  original_reference_id: PMID:39584160
  qualifier: enables
  review:
    summary: PALB2 self-associates via a coiled-coil-mediated dimerization, stabilized by
      its intrinsically disordered regions. Experimentally demonstrated.
    action: ACCEPT
    reason: Direct biophysical evidence for coiled-coil-mediated homodimerization, a
      property important for focal accumulation at DNA breaks.
    supported_by:
    - reference_id: PMID:39584160
      supporting_text: Coiled-coil mediated dimerization is stabilized by interaction between
        intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IMP
  original_reference_id: PMID:39584160
  qualifier: enables
  review:
    summary: Mutational evidence supporting PALB2 self-association/dimerization. Consistent
      with the EXP annotation from the same study.
    action: ACCEPT
    reason: Corroborates the homodimerization activity; retained for consistency with the
      EXP annotation.
    supported_by:
    - reference_id: PMID:39584160
      supporting_text: Coiled-coil mediated dimerization is stabilized by interaction between
        intrinsically disordered regions (IDRs) leading to a 2-fold structural compaction.
- term:
    id: GO:0003697
    label: single-stranded DNA binding
  evidence_type: EXP
  original_reference_id: PMID:39584160
  qualifier: enables
  review:
    summary: ssDNA binding by the PALB2-DBD, which also drives its structural compaction
      and tetramerization. Consistent with the IMP ssDNA-binding annotation.
    action: ACCEPT
    reason: Direct experimental evidence for ssDNA binding by PALB2.
    supported_by:
    - reference_id: PMID:39584160
      supporting_text: Single-stranded (ss)DNA binding promotes additional structural compaction
        and protein tetramerization.
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: EXP
  original_reference_id: PMID:39584160
  qualifier: involved_in
  review:
    summary: ssDNA binding promotes PALB2 tetramerization in vitro, proposed to underlie a
      strand-exchange mechanism. Genuine but specialized higher-order self-assembly.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported oligomeric state, but a mechanistic detail of PALB2
      self-assembly rather than a core molecular function on its own; retained as non-core.
    supported_by:
    - reference_id: PMID:39584160
      supporting_text: Single-stranded (ss)DNA binding promotes additional structural compaction
        and protein tetramerization.
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IPI
  original_reference_id: PMID:39584160
  qualifier: enables
  review:
    summary: DNA binding annotated via interaction with a DNA substrate (ChEBI:9160).
      Consistent with the other DNA-binding annotations for PALB2.
    action: ACCEPT
    reason: Corroborates PALB2 DNA binding; retained for consistency with the EXP/IDA/IBA
      DNA-binding annotations.
    supported_by:
    - reference_id: PMID:39584160
      supporting_text: the PALB2 DNA-binding domain (PALB2-DBD) supports DNA strand exchange
        in vitro
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:16793542
  qualifier: located_in
  review:
    summary: Experimental nuclear localization from the founding PALB2 study. Correct.
    action: ACCEPT
    reason: Direct experimental evidence of nuclear localization.
    supported_by:
    - reference_id: PMID:16793542
      supporting_text: PALB2 colocalizes with BRCA2 in nuclear foci
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:26833090
  qualifier: located_in
  review:
    summary: Experimental nuclear localization within the XPG-BRCA2-PALB2 HR complex study.
      Correct.
    action: ACCEPT
    reason: Direct experimental localization evidence; PALB2 is chromatin-associated and
      forms damage-induced foci.
    supported_by:
    - reference_id: PMID:26833090
      supporting_text: XPG depletion reduces their chromatin binding and subsequent RAD51
        foci formation
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:28319063
  qualifier: located_in
  review:
    summary: Experimental nuclear localization consistent with PALB2 focus formation at
      DNA damage sites. Correct.
    action: ACCEPT
    reason: Direct experimental localization evidence; PALB2 forms ionizing radiation-induced
      nuclear foci.
    supported_by:
    - reference_id: PMID:28319063
      supporting_text: wt PALB2 forms IRIF that largely co-localize with those of BRCA1
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9704408
  qualifier: located_in
  review:
    summary: Reactome-asserted nucleoplasm location (HR pathway module). Consistent with
      PALB2's site of action.
    action: ACCEPT
    reason: Correct location; PALB2 acts in the nucleoplasm during HR.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9704330
  qualifier: located_in
  review:
    summary: Reactome-asserted nucleoplasm location (defective HR module). Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26833090
  qualifier: enables
  review:
    summary: Interactions within the ERCC5/XPG-BRCA2-PALB2-DSS1-RAD51 HR complex (withs
      include XPG, BRCA2, RAD51). Real complex membership, uninformative generic term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The specific complex membership is captured by the protein-containing-complex
      annotation from the same paper; protein binding itself is uninformative.
    supported_by:
    - reference_id: PMID:26833090
      supporting_text: XPG directly interacts with BRCA2, RAD51, and PALB2, and XPG depletion
        reduces their chromatin binding and subsequent RAD51 foci formation.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:26833090
  qualifier: part_of
  review:
    summary: PALB2 is a component of an HR complex (ERCC5/XPG, BRCA2, PALB2, DSS1, RAD51).
      "Protein-containing complex" is very generic; a DNA repair complex term is more
      informative.
    action: MODIFY
    reason: Replace the top-level generic complex term with the more specific DNA repair
      complex, matching the HR complex demonstrated here and the BRCA1-PALB2-BRCA2 complex.
    proposed_replacement_terms:
    - id: GO:1990391
      label: DNA repair complex
    supported_by:
    - reference_id: PMID:26833090
      supporting_text: XPG directly interacts with BRCA2, RAD51, and PALB2
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IMP
  original_reference_id: PMID:26323318
  qualifier: involved_in
  review:
    summary: HR annotation from a study (NUCKS1/RAD51AP1) that used PALB2 depletion within
      its HR (gene-conversion) assays. HR is the well-established core process for PALB2.
    action: ACCEPT
    reason: HR is unambiguously PALB2's core function; per guidelines an experimental
      annotation is not removed for lack of cached full text, and the assigned process is
      clearly correct and directly assayed here.
    supported_by:
    - reference_id: PMID:26323318
      supporting_text: knockdown of PALB2 by one of two different siRNAs elicits a more
        dramatic effect on gene conversion frequency than depletion of either NUCKS1 or
        RAD51AP1
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5685838
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location (HR/D-loop pathway). Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686410
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686440
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686469
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5686483
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693539
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693584
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693589
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693593
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693620
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location for the "D-loop formation mediated by PALB2,
      BRCA2 and RAD51" reaction. Directly relevant and consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location; this reaction is a canonical PALB2 HR step.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9701199
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location (defective D-loop formation module). Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9709601
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location. Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9853389
  qualifier: located_in
  review:
    summary: Reactome nucleoplasm location (FIGNL1 binds RAD51 module). Consistent.
    action: ACCEPT
    reason: Correct nucleoplasmic location.
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IDA
  original_reference_id: PMID:19369211
  qualifier: involved_in
  review:
    summary: Direct assay evidence that disrupting the BRCA1-PALB2 interaction causes
      defective HR. Core function.
    action: ACCEPT
    reason: Direct experimental support for PALB2's essential role in HR repair.
    supported_by:
    - reference_id: PMID:19369211
      supporting_text: cells harboring mutations with abrogated BRCA1-PALB2 interaction
        resulted in defective homologous recombination (HR) repair
- term:
    id: GO:0000724
    label: double-strand break repair via homologous recombination
  evidence_type: IDA
  original_reference_id: PMID:19423707
  qualifier: involved_in
  review:
    summary: PALB2 chromatin association and oligomerization are required to anchor the
      BRCA2·RAD51 machinery at breaks for HR. Core function.
    action: ACCEPT
    reason: Direct experimental evidence linking PALB2 focal accumulation to proficient HR.
    supported_by:
    - reference_id: PMID:19423707
      supporting_text: PALB2 exists as homo-oligomers and that PALB2 oligomerization is
        essential for its focal accumulation at DNA breaks in vivo
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IDA
  original_reference_id: PMID:20871616
  qualifier: enables
  review:
    summary: Purified PALB2 binds ssDNA, dsDNA and D-loop (preference D-loop > dsDNA >
      ssDNA) via its N-terminal half. Direct biochemical evidence.
    action: ACCEPT
    reason: Direct in vitro demonstration of PALB2 DNA-binding activity.
    supported_by:
    - reference_id: PMID:20871616
      supporting_text: 'Full length PALB2 bound all three species of DNA with the following
        preference: D-loop > dsDNA > ssDNA'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19423707
  qualifier: enables
  review:
    summary: Interaction with BRCA2 (P51587); PALB2 refines its BRCA2-binding motif to the
      WD40 repeats and its chromatin association is a prerequisite for BRCA2 loading. Part
      of the adaptor/scaffold function.
    action: MODIFY
    reason: BRCA2-binding interaction central to PALB2's adaptor role; replace generic
      protein binding with protein-macromolecule adaptor activity.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    supported_by:
    - reference_id: PMID:19423707
      supporting_text: PALB2 localizes to chromatin and assembled as oligomers at the site
        of DNA damage, which then serves as an anchor for the loading of BRCA2 and RAD51
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20332121
  qualifier: enables
  review:
    summary: Direct interaction with MORF4L1/MRG15 (chromodomain protein), which promotes
      chromatin-associated homology-directed repair. Peripheral chromatin-targeting
      interaction with an uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: A genuine chromatin-targeting interaction, but a supporting rather than core
      role; protein binding is uninformative as a molecular function.
    supported_by:
    - reference_id: PMID:20332121
      supporting_text: PALB2 binds directly to a conserved chromodomain protein, MRG15
- term:
    id: GO:0031491
    label: nucleosome binding
  evidence_type: IDA
  original_reference_id: PMID:22193777
  qualifier: enables
  review:
    summary: >-
      PALB2's chromatin-association motif (ChAM) directly and intrinsically binds
      nucleosomes, mediating constitutive chromatin association that is distinct from the
      N-terminal DNA-binding regions. ChAM deletion reduces PALB2 and RAD51 accumulation at
      DNA-damage sites and confers mitomycin C hypersensitivity.
    action: NEW
    reason: >-
      A genuine, experimentally demonstrated molecular function (direct nucleosome binding by
      the ChAM motif) that is absent from GOA and was previously reflected only as
      uninformative "protein binding" (PMID:22193777 row above). Added as a NEW annotation but
      kept non-core: ChAM-mediated nucleosome/chromatin association is a targeting/anchoring
      activity that helps retain and position the BRCA1-PALB2-BRCA2 complex on chromatin,
      rather than the central molecular-adaptor function itself.
    supported_by:
    - reference_id: PMID:22193777
      supporting_text: ChAM robustly binds to nucleosomes
    - reference_id: PMID:22193777
      supporting_text: >-
        chromatin-association motif (ChAM), an evolutionarily conserved motif in PALB2, is
        necessary and sufficient to mediate its chromatin association in both unperturbed and
        damaged cells
core_functions:
- description: Molecular adaptor/scaffold that physically bridges BRCA1 (via its N-terminal
    coiled-coil) and BRCA2 (via its C-terminal WD40 β-propeller), forming the
    BRCA1-PALB2-BRCA2 complex that localizes and stabilizes BRCA2 at damaged chromatin and
    promotes RAD51 loading for homologous recombination.
  supported_by:
  - reference_id: PMID:19369211
    supporting_text: PALB2, the partner and localizer of BRCA2, binds directly to BRCA1,
      and serves as the molecular scaffold in the formation of the BRCA1-PALB2-BRCA2
      complex.
  - reference_id: PMID:39584160
    supporting_text: The partner and localizer of BRCA2 (PALB2) is a scaffold protein
      linking BRCA1 with BRCA2 and RAD51 during homologous recombination (HR).
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  directly_involved_in:
  - id: GO:0000724
    label: double-strand break repair via homologous recombination
  locations:
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:1990391
    label: DNA repair complex
- description: >-
    DNA-binding activity of the intrinsically disordered N-terminal domain (preference D-loop >
    dsDNA > ssDNA) that stimulates RAD51-mediated strand invasion and D-loop formation,
    promoting homologous recombination; the domain also has intrinsic strand-exchange activity
    and cooperates with RAD51AP1. The MF term is GO:0000217 DNA secondary structure binding
    rather than the bare GO:0003677 DNA binding, because the quoted evidence is a documented
    structural preference (D-loop over duplex over single-stranded) rather than
    sequence-independent DNA binding - the same reasoning applied to FANCI in this cohort.
  supported_by:
  - reference_id: PMID:20871616
    supporting_text: 'Full length PALB2 bound all three species of DNA with the following
      preference: D-loop > dsDNA > ssDNA'
  - reference_id: PMID:31017574
    supporting_text: We identified a major DNA-binding site of PALB2, mutations in which
      reduce RAD51 foci formation and the overall HDR efficiency in cells by 50%.
  molecular_function:
    id: GO:0000217
    label: DNA secondary structure binding
  directly_involved_in:
  - id: GO:0000724
    label: double-strand break repair via homologous recombination
  locations:
  - id: GO:0005654
    label: nucleoplasm
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:16793542
  title: Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Founding PALB2 paper; establishes BRCA2 binding, nuclear localization,
      and that PALB2 promotes BRCA2 localization/stability and its HR/checkpoint functions.
- id: PMID:17420451
  title: Analysis of PALB2/FANCN-associated breast cancer families.
  findings: []
- id: PMID:19369211
  title: PALB2 is an integral component of the BRCA complex required for homologous
    recombination repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes PALB2 as the direct BRCA1-binding molecular scaffold/adaptor
      forming the BRCA1-PALB2-BRCA2 complex required for HR.
- id: PMID:19423707
  title: PALB2 regulates recombinational repair through chromatin association and
    oligomerization.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Demonstrates PALB2 chromatin association and coiled-coil-mediated
      oligomerization anchoring BRCA2·RAD51 at breaks; maps BRCA2 binding to the WD40 repeats.
- id: PMID:19609323
  title: Structural basis for recruitment of BRCA2 by PALB2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystal structure of the PALB2 WD40 β-propeller bound to a BRCA2 peptide;
      defines the BRCA2-recruitment interface.
- id: PMID:20332121
  title: MRG15 binds directly to PALB2 and stimulates homology-directed repair of
    chromosomal breaks.
  findings: []
- id: PMID:20871616
  title: Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Biochemical demonstration that PALB2 binds DNA (D-loop > dsDNA > ssDNA),
      interacts with RAD51, and stimulates RAD51 D-loop formation, cooperating with RAD51AP1.
- id: PMID:22193777
  title: ChAM, a novel motif that mediates PALB2 intrinsic chromatin binding and facilitates
    DNA repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text confirms PALB2's ChAM motif is necessary and sufficient for
      intrinsic chromatin association and directly binds nucleosomes (distinct from the
      DNA-binding regions); ChAM deletion reduces PALB2/RAD51 focus formation and confers
      mitomycin C hypersensitivity. Basis for the NEW nucleosome-binding (GO:0031491)
      annotation.
- id: PMID:22244764
  title: 'Structural basis for molecular interactions involving MRG domains: implications
    in chromatin biology.'
  findings: []
- id: PMID:22293751
  title: APRIN is a cell cycle specific BRCA2-interacting protein required for genome
    integrity and a predictor of outcome after chemotherapy in breast cancer.
  findings: []
- id: PMID:22331464
  title: PALB2 interacts with KEAP1 to promote NRF2 nuclear accumulation and function.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Primary mechanistic paper for PALB2's secondary, HR-independent role;
      PALB2 uses a conserved ETGE-type motif to compete with NRF2 for KEAP1, promoting NRF2
      nuclear accumulation and lowering ROS. Cited to ground the KEAP1 interaction rows that
      otherwise rest only on high-throughput interactome hits.
- id: PMID:24141787
  title: Breast cancer-associated missense mutants of the PALB2 WD40 domain, which
    directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Shows the PALB2 WD40 domain directly and independently binds RAD51C,
      RAD51, BRCA2 and XRCC3, scaffolding an HR complex; breast-cancer missense variants
      disrupt these interactions and DNA repair.
- id: PMID:24485656
  title: Breast cancer proteins PALB2 and BRCA2 stimulate polymerase η in recombination-associated
    DNA synthesis at blocked replication forks.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PALB2 and BRCA2 interact with POLH and stimulate its DNA synthesis at
      blocked replication forks; a specialized replication-associated HR role.
- id: PMID:25960410
  title: Structural Basis for Multi-specificity of MRG Domains.
  findings: []
- id: PMID:26323318
  title: NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination
    and genome stability.
  findings: []
- id: PMID:26833090
  title: Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination
    and Genome Stability.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Places PALB2 in an ERCC5/XPG-BRCA2-PALB2-DSS1-RAD51 HR complex; XPG
      directly interacts with PALB2, BRCA2 and RAD51.
- id: PMID:28319063
  title: Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Identifies the PALB2 L35P variant that abrogates BRCA1 binding and HR,
      confirming the coiled-coil BRCA1-PALB2 bridge and its clinical relevance.
- id: PMID:28398198
  title: Functional and mutational landscapes of BRCA1 for homology-directed repair
    and therapy resistance.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Shows the BRCA1-PALB2 interaction dictates the choice between HR and
      single-strand annealing.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:29656893
  title: DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and
    PARP Inhibitor Sensitivity.
  findings: []
- id: PMID:30410870
  title: Two Missense Variants Detected in Breast Cancer Probands Preventing BRCA2-PALB2
    Protein Interaction.
  findings: []
- id: PMID:31017574
  title: Novel RNA and DNA strand exchange activity of the PALB2 DNA binding domain
    and its critical role for DNA repair in cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Maps a major PALB2 DNA-binding site required for RAD51 foci and HDR, and
      shows the N-DBD has intrinsic strand-exchange activity on DNA and RNA.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34591612
  title: A protein interaction landscape of breast cancer.
  findings: []
- id: PMID:39584160
  title: The strand exchange domain of tumor suppressor PALB2 is intrinsically disordered
    and promotes oligomerization-dependent DNA compaction.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Characterizes the PALB2-DBD as intrinsically disordered; coiled-coil
      dimerization plus ssDNA-driven tetramerization underlie DNA compaction and strand
      exchange; frames PALB2 as the BRCA1-BRCA2-RAD51 scaffold.
- id: Reactome:R-HSA-5685838
  title: CX3 complex binds D-loop structures
  findings: []
- id: Reactome:R-HSA-5686410
  title: BLM mediates dissolution of double Holliday junction
  findings: []
- id: Reactome:R-HSA-5686440
  title: MUS81:EME1,EME2 cleaves D-loop
  findings: []
- id: Reactome:R-HSA-5686469
  title: Resolution of D-loops cleaved by MUS81:EME1 or MUS81:EME2
  findings: []
- id: Reactome:R-HSA-5686483
  title: Resolution of Holliday junctions cleaved by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)
  findings: []
- id: Reactome:R-HSA-5693539
  title: Ligation of DNA and formation of Holliday structures following repair synthesis
  findings: []
- id: Reactome:R-HSA-5693584
  title: Cleavage of Holliday junctions by GEN1 or SLX1A:SLX4:MUS81:EME1,(MUS81:EME2)
  findings: []
- id: Reactome:R-HSA-5693589
  title: D-loop dissociation and strand annealing
  findings: []
- id: Reactome:R-HSA-5693593
  title: D-loop extension by DNA polymerases
  findings: []
- id: Reactome:R-HSA-5693620
  title: D-loop formation mediated by PALB2, BRCA2 and RAD51
  findings: []
- id: Reactome:R-HSA-9701199
  title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
    of BRCA1 in PALB2 binding
  findings: []
- id: Reactome:R-HSA-9704330
  title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
    of PALB2 in BRCA1 binding
  findings: []
- id: Reactome:R-HSA-9704408
  title: Defective D-loop formation mediated by PALB2, BRCA2 and RAD51 due to loss-of-function
    of PALB2 in binding to BRCA2/RAD51/RAD51C
  findings: []
- id: Reactome:R-HSA-9709601
  title: Defective recruitment of BRCA2 and RAD51 due to loss of BRCA2 function in
    PALB2 binding
  findings: []
- id: Reactome:R-HSA-9853389
  title: FIGNL1 binds RAD51
  findings: []
suggested_questions:
- question: Beyond its scaffold role, how much of PALB2's direct DNA binding and intrinsic
    strand-exchange activity contributes to HR in vivo versus in vitro?
- question: What is the physiological significance of the KEAP1-PALB2 interaction relative
    to PALB2's dominant HR-scaffold function?
suggested_experiments:
- description: Generate separation-of-function PALB2 alleles that selectively disrupt DNA
    binding versus BRCA1 or BRCA2 binding, and assay HR efficiency, RAD51 foci formation,
    and PARP-inhibitor sensitivity to dissect the DNA-binding contribution from the
    adaptor/scaffold contribution.
- description: Structural and biophysical characterization (cryo-EM/SAXS) of the full
    BRCA1-PALB2-BRCA2 assembly on damaged chromatin to define the stoichiometry and
    geometry of the adaptor bridge.

PALB2

Gene Description