Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0003684 damaged DNA binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of damaged-DNA binding, the core molecular function of DDB2 as the UV-lesion sensor of the UV-DDB complex. Reason: Core molecular function, directly supported experimentally (UV-DDB binds CPDs/6-4PPs) and conserved across orthologs. Structural work shows the WD40 propeller flips the damaged bases out and kinks the duplex by ~40 degrees, the structural basis of lesion recognition. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway file:human/DDB2/DDB2-deep-research-falcon.md DDB2 contacts ~7 bp around the lesion and induces an approximately 40° DNA kink with local strand separation. The DDB1–DDB2 interface is large (reported ~3900 Å²), consistent with stable heterodimerization.
GO:0003684 damaged DNA binding	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based electronic assignment of damaged-DNA binding, redundant with the experimentally supported core function. Reason: Correct core molecular function; redundant with IDA/IBA/TAS evidence. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assignment of nuclear localization, the core compartment for DDB2's DNA-repair function. Reason: Correct core localization; redundant with multiple EXP/IDA annotations. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005694 chromosome	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of chromosome localization from the UniProt subcellular location; DDB2 accumulates on damaged chromatin/chromosomes after UV. Reason: Correct localization; DDB2 acts on chromatinized DNA at damage sites; redundant with the EXP chromosome annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Chromosome {ECO:0000269\|PubMed:32789493}. Note=Accumulates at sites of DNA damage following UV irradiation.
GO:0006281 DNA repair	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic assignment of the general DNA repair process, a parent of the specific nucleotide-excision repair role of DDB2. Reason: Correct but generic; the specific GO:0006289 (nucleotide-excision repair) / GG-NER better captures the core role. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Protein, which is both involved in DNA repair and protein ubiquitination
GO:0034644 cellular response to UV	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine-learning assignment of cellular response to UV, consistent with DDB2's role as the UV-lesion sensor. Reason: Correct core process; DDB2 senses UV photolesions and initiates the response; redundant with EXP/ISS evidence. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt a complex that recognizes UV-induced DNA damage
GO:0080008 Cul4-RING E3 ubiquitin ligase complex	IEA GO_REF:0000002	ACCEPT	Summary: InterPro-based assignment of DDB2 as part of a CUL4-RING E3 ubiquitin ligase complex (CRL4(DDB2)), its core substrate-receptor context. Reason: Core complex membership; DDB2 is the substrate-recognition (DCAF) module of CRL4(DDB2); redundant with EXP/IMP evidence. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Also functions as the substrate recognition module for the DCX (DDB2-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1
GO:0005515 protein binding	IPI PMID:16473935 The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderm...	KEEP AS NON CORE	Summary: IntAct interactions with DDB1 (Q16531) and CUL4A (Q13619) from the XP-E/H2A study, reflecting CRL4(DDB2) assembly. Bare protein binding is uninformative. Reason: Records real, functionally important complex partners (DDB1, CUL4A) but the bare protein binding term is uninformative per curation guidelines; captured by the complex part_of annotations. Supporting Evidence: PMID:16473935 The UV-DDB complex is a component of the newly identified cullin 4A-based ubiquitin E3 ligase, DDB1-CUL4A(DDB2)
GO:0005515 protein binding	IPI PMID:17041588 CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repe...	KEEP AS NON CORE	Summary: Interactions with DDB1 and CUL4A from a study of CUL4-DDB1 WD40-repeat partners. Bare protein binding is uninformative. Reason: Real complex interactions but bare protein binding is uninformative; captured by complex part_of annotations. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0005515 protein binding	IPI PMID:17360488 HIV-1 Vpr function is mediated by interaction with the damag...	KEEP AS NON CORE	Summary: Interaction with DDB1 (Q16531) captured in a study of HIV-1 Vpr/DDB1. Bare protein binding is uninformative. Reason: Real DDB1 interaction but bare protein binding is uninformative; the DDB1 association is captured by complex membership. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Component of the UV-DDB complex which includes DDB1 and DDB2
GO:0005515 protein binding	IPI PMID:19109893 Structural basis of UV DNA-damage recognition by the DDB1-DD...	KEEP AS NON CORE	Summary: Interaction with DDB1 (Q16531) from the UV-DDB crystal-structure study. Bare protein binding is uninformative. Reason: Real DDB1 interaction underpinning the structural basis of damage recognition, but bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Component of the UV-DDB complex which includes DDB1 and DDB2
GO:0005515 protein binding	IPI PMID:19966799 A promiscuous alpha-helical motif anchors viral hijackers an...	KEEP AS NON CORE	Summary: Interaction with DDB1 (Q16531) from a study of the helical motif anchoring DCAFs/viral hijackers to CUL4-DDB1. Bare protein binding is uninformative. Reason: Real DDB1 interaction relevant to DCAF anchoring, but bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt DDB2 may function as the substrate recognition module within this complex
GO:0005515 protein binding	IPI PMID:21145461 Dynamics of cullin-RING ubiquitin ligase network revealed by...	KEEP AS NON CORE	Summary: Interaction with CUL4A (Q13619) from a quantitative proteomics study of the CRL network. Bare protein binding is uninformative. Reason: Real CRL network interaction but bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0005515 protein binding	IPI PMID:22039351 Regulation of nucleotide excision repair by UV-DDB: prioriti...	KEEP AS NON CORE	Summary: Interactions with XPC (Q01831-1) and DDB1 (Q16531) from a study of UV-DDB prioritization of internucleosomal damage recognition. Bare protein binding is uninformative. Reason: Records the functionally meaningful DDB2-XPC handoff interaction and DDB1 binding, but bare protein binding is uninformative. Supporting Evidence: PMID:22039351 UV-DDB
GO:0005515 protein binding	IPI PMID:22822215 Damaged DNA induced UV-damaged DNA-binding protein (UV-DDB) ...	KEEP AS NON CORE	Summary: Interaction with DDB1 (Q16531) from the UV-DDB dimerization study. Bare protein binding is uninformative. Reason: Real DDB1 interaction but bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Component of the UV-DDB complex which includes DDB1 and DDB2
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	KEEP AS NON CORE	Summary: Interaction with CUL4A (Q13619) from a quantitative interactome study. Bare protein binding is uninformative. Reason: High-throughput CRL interaction; bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: Interactions with DDB1 and CUL4A from a large-scale interactome study. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0005515 protein binding	IPI PMID:30945288 Inflammation-dependent overexpression of c-Myc enhances CRL4...	KEEP AS NON CORE	Summary: Interaction with CUL4A (Q13619) captured in a CRL4(DCAF4) study. Bare protein binding is uninformative. Reason: High-throughput/CRL-context interaction; bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Interaction (P40337-2, VHL isoform) from a neurodegeneration interactome study. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Protein, which is both involved in DNA repair and protein ubiquitination
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Interactions with DDB1, CUL4A and others from a cell-specific interactome study. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	KEEP AS NON CORE	Summary: Interaction with DDB1 (Q16531) from the OpenCell endogenous-tagging interactome. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Component of the UV-DDB complex which includes DDB1 and DDB2
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Interaction with CUL4A (Q13619) from a multimodal cell-map interactome study. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0005515 protein binding	IPI PMID:9418871 DDB, a putative DNA repair protein, can function as a transc...	KEEP AS NON CORE	Summary: Interaction with E2F1 (Q01094) and DDB1 (Q16531) reported in a study of DDB as a transcriptional partner of E2F1. Bare protein binding is uninformative. Reason: Records a real interaction (E2F1) supporting a peripheral transcriptional-partner role, but bare protein binding is uninformative. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Protein, which is both involved in DNA repair and protein ubiquitination
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway-derived general protein-ubiquitination process, a parent of the specific CRL4(DDB2)-mediated ubiquitination of histones/XPC. Reason: Correct but generic; the substrate-receptor role within CRL4(DDB2) and specific histone/XPC ubiquitination better capture the function. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0005634 nucleus	IDA PMID:14751237 Human DDB2 splicing variants are dominant negative inhibitor...	ACCEPT	Summary: Direct (ComplexPortal-curated) nuclear localization of DDB2. Core compartment. Reason: Core localization with direct support; DDB2 acts in the nucleus on damaged chromatin. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005634 nucleus	NAS PMID:22118460 The molecular basis of CRL4DDB2/CSA ubiquitin ligase archite...	ACCEPT	Summary: Non-traceable author statement of nuclear localization, consistent with DDB2's core compartment. Reason: Correct core localization; redundant with multiple experimental annotations. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0006974 DNA damage response	ISS GO_REF:0000114	KEEP AS NON CORE	Summary: Sequence/complex-similarity transfer of DNA damage response to the UV-DDB complex (CPX-477). A parent process of DDB2's specific UV-lesion-recognition role. Reason: Correct but generic relative to the specific GG-NER / cellular response to UV roles. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt a complex that recognizes UV-induced DNA damage
GO:0006974 DNA damage response	EXP PMID:22118460 The molecular basis of CRL4DDB2/CSA ubiquitin ligase archite...	KEEP AS NON CORE	Summary: Experimental (ComplexPortal) annotation of DNA damage response for CRL4(DDB2). A parent process of DDB2's specific UV-lesion role. Reason: Correct but generic; the specific nucleotide-excision repair / cellular response to UV annotations better capture the core role. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex	EXP PMID:22118460 The molecular basis of CRL4DDB2/CSA ubiquitin ligase archite...	ACCEPT	Summary: Experimental membership of DDB2 in the CUL4A-RING (CRL4A(DDB2)) ligase complex, its core substrate-receptor context. Reason: Core complex membership with experimental support; DDB2 is the DCAF substrate receptor of CRL4A. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt the DCX (DDB2-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1
GO:0034644 cellular response to UV	ISS GO_REF:0000114	ACCEPT	Summary: Complex-similarity transfer of cellular response to UV. Consistent with DDB2's UV-lesion-sensing role. Reason: Correct core process; redundant with EXP evidence. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt a complex that recognizes UV-induced DNA damage
GO:0034644 cellular response to UV	EXP PMID:22118460 The molecular basis of CRL4DDB2/CSA ubiquitin ligase archite...	ACCEPT	Summary: Experimental annotation of cellular response to UV for CRL4(DDB2), reflecting DDB2's role as the UV-lesion sensor. Reason: Core process with experimental support. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt a complex that recognizes UV-induced DNA damage
GO:0070914 UV-damage excision repair	IDA PMID:14751237 Human DDB2 splicing variants are dominant negative inhibitor...	ACCEPT	Summary: Direct evidence that DDB2 functions in UV-damaged DNA repair; splice variants D1/D2 act as dominant-negative inhibitors of this process. Reason: Core biological process; the dominant-negative variants demonstrate DDB2's requirement for UV-damage repair. Supporting Evidence: PMID:14751237 D1 and D2 are dominant negative inhibitors of DNA repair
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence (HPA) evidence for nucleoplasmic localization, consistent with DDB2's nuclear site of action. Reason: Correct localization with IDA support; consistent with the core nuclear/chromatin compartment. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005634 nucleus	EXP PMID:11705987 DDB accumulates at DNA damage sites immediately after UV irr...	ACCEPT	Summary: Experimental evidence that DDB accumulates in the nucleus at DNA damage sites after UV. Core compartment. Reason: Core localization with experimental support. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005634 nucleus	EXP PMID:12944386 In vivo recruitment of XPC to UV-induced cyclobutane pyrimid...	ACCEPT	Summary: Experimental nuclear localization of the DDB2 (p48) gene product at UV-irradiated sites. Core compartment. Reason: Core localization with experimental support. Supporting Evidence: PMID:12944386 p48 localized to UV-irradiated sites that contained either CPDs or 6-4PPs
GO:0005634 nucleus	EXP PMID:16473935 The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderm...	ACCEPT	Summary: Experimental nuclear localization within the XP-E/H2A ubiquitination study. Core compartment. Reason: Core localization with experimental support. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005634 nucleus	EXP PMID:18593899 The cullin 4B-based UV-damaged DNA-binding protein ligase bi...	ACCEPT	Summary: Experimental nuclear localization within the CUL4B-based UV-DDB ligase / H2A ubiquitination study. Core compartment. Reason: Core localization with experimental support. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005694 chromosome	EXP PMID:32789493 The deacetylase SIRT6 promotes the repair of UV-induced DNA ...	ACCEPT	Summary: Experimental chromosome localization (SIRT6/DDB2 study); DDB2 accumulates on damaged chromatin/chromosomes after UV. Core localization. Reason: Core localization; DDB2 binds chromatinized damaged DNA at chromosomes. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Chromosome {ECO:0000269\|PubMed:32789493}. Note=Accumulates at sites of DNA damage following UV irradiation.
GO:0000785 chromatin	ISS PMID:33937266 USP44 Stabilizes DDB2 to Facilitate Nucleotide Excision Repa...	ACCEPT	Summary: Sequence-similarity assignment that DDB2 is active in chromatin, where it binds CPDs and the CRL4(DDB2) ligase acts on damaged nucleosomes. Reason: Correct core localization of activity; DDB2 binds and acts on damaged chromatin to recruit XPC. Supporting Evidence: PMID:33937266 DDB2 must remain on damaged chromatin, however, for sufficient time to recruit and hand-off lesions to XPC
GO:0003684 damaged DNA binding	ISS PMID:33937266 USP44 Stabilizes DDB2 to Facilitate Nucleotide Excision Repa...	ACCEPT	Summary: Sequence-similarity transfer of damaged-DNA binding, the core molecular function of DDB2. Reason: Core molecular function; redundant with IDA/IBA/TAS evidence. Supporting Evidence: PMID:33937266 DDB2 directly binds CPDs and subsequently undergoes ubiquitination and proteasomal degradation
GO:0006289 nucleotide-excision repair	ISS PMID:33937266 USP44 Stabilizes DDB2 to Facilitate Nucleotide Excision Repa...	ACCEPT	Summary: Sequence-similarity assignment of nucleotide-excision repair, the core biological process of DDB2 (UV-lesion recognition initiating GG-NER). Reason: Core biological process; redundant with IDA/TAS evidence. Supporting Evidence: PMID:33937266 The ubiquitin E3-ligase complex UV-DDB is required for the recognition and repair of UV-induced cyclobutane pyrimidine dimers (CPDs) lesions through NER
GO:0006289 nucleotide-excision repair	IDA PMID:19109893 Structural basis of UV DNA-damage recognition by the DDB1-DD...	ACCEPT	Summary: Direct evidence (structural study of UV-DDB on damaged DNA) for DDB2's role in nucleotide-excision repair via lesion recognition. Core process. Reason: Core biological process with direct support. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair
GO:0090734 site of DNA damage	IDA PMID:19109893 Structural basis of UV DNA-damage recognition by the DDB1-DD...	ACCEPT	Summary: Direct evidence that DDB2 is active at sites of DNA damage, where the UV-DDB complex binds photolesions. Core localization of activity. Reason: Correct localization of activity; DDB2 binds and acts at UV-damage sites. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Accumulates at sites of DNA damage following UV irradiation
GO:0003684 damaged DNA binding	IDA PMID:22334663 Monoubiquitinated histone H2A destabilizes photolesion-conta...	ACCEPT	Summary: Direct evidence that DDB2 (within UV-DDB) binds photolesion-containing nucleosomes/damaged DNA. Core molecular function. Reason: Core molecular function with direct support. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP)
GO:0005515 protein binding	IPI PMID:16949367 A family of diverse Cul4-Ddb1-interacting proteins includes ...	KEEP AS NON CORE	Summary: Interactions with DDB1, CUL4A and CUL4B from the DCAF-family study identifying DDB2 as a Cul4-Ddb1-associated substrate receptor. Bare protein binding is uninformative. Reason: Real complex interactions establishing DDB2 as a DCAF, but bare protein binding is uninformative; captured by complex part_of annotations. Supporting Evidence: PMID:16949367 we identify 18 Ddb1- and Cul4-associated factors (DCAFs)
GO:0080008 Cul4-RING E3 ubiquitin ligase complex	IMP PMID:16949367 A family of diverse Cul4-Ddb1-interacting proteins includes ...	ACCEPT	Summary: Mutant-phenotype evidence that DDB2 is part of a CUL4-RING E3 ligase complex (as a DCAF), its core substrate-receptor context. Reason: Core complex membership; DDB2 is a CUL4-DDB1-associated factor (DCAF) substrate receptor. Supporting Evidence: PMID:16949367 we identify 18 Ddb1- and Cul4-associated factors (DCAFs)
GO:0044877 protein-containing complex binding	IPI PMID:11564863 Human STAGA complex is a chromatin-acetylating transcription...	KEEP AS NON CORE	Summary: DDB2 binds the STAGA chromatin-acetylating coactivator complex (ComplexPortal CPX-900). A real but peripheral complex association. Reason: Documents association with the STAGA complex (DDB connecting DNA-damage-binding to a transcriptional coactivator), peripheral to the core GG-NER/CRL4 role. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Protein, which is both involved in DNA repair and protein ubiquitination
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5696997	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization within a GG-NER/CRL4 reaction (USP24 deubiquitinates DDB2). Consistent with the core nuclear compartment. Reason: Correct localization; redundant with IDA nucleoplasm and multiple nuclear annotations. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5689317	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in GG-NER pre-incision complex formation. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5689861	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (XPA recruitment). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5690213	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5690988	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER incision reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5690990	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER incision reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5690991	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5690996	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5691000	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5696655	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (PARP1/2 PARylates DDB2). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5696670	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (CHD1L recruitment). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6790454	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER/XPC SUMOylation reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6790487	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (RNF111 ubiquitinates SUMOylated XPC). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0031465 Cul4B-RING E3 ubiquitin ligase complex	IDA PMID:22334663 Monoubiquitinated histone H2A destabilizes photolesion-conta...	ACCEPT	Summary: Direct evidence of DDB2 in the CUL4B-RING (CRL4B(DDB2)) ligase, which acts on photolesion-containing nucleosomes. Core complex membership. Reason: Core complex membership; DDB2 is the substrate receptor of both CUL4A- and CUL4B-based CRL4(DDB2) ligases. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
GO:0070914 UV-damage excision repair	IDA PMID:22334663 Monoubiquitinated histone H2A destabilizes photolesion-conta...	ACCEPT	Summary: Direct evidence linking DDB2/UV-DDB E3 ligase to UV-damage excision repair via monoubiquitinated-H2A-dependent nucleosome destabilization and ligase release. Reason: Core biological process with direct support. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5691006	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (XPC:RAD23:CETN2 and UV-DDB bind distorted dsDNA). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5696664	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (PARP1/2 binds DDB2). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6782943	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in the GG-NER reaction in which UV-DDB ubiquitinates XPC. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6806423	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in the reaction TP53 stimulates DDB2 expression. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8952638	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 neddylation reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8952639	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 neddylation reaction. Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8955245	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 regulation reaction (CAND1 binds CRL4). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8955285	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 regulation reaction (COMMDs displace CAND1). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8956045	ACCEPT	Summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 regulation reaction (COP9 signalosome deneddylates CRL4). Reason: Correct localization; redundant with IDA nucleoplasm annotation. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0000209 protein polyubiquitination	IDA PMID:12732143 The ubiquitin ligase activity in the DDB2 and CSA complexes ...	ACCEPT	Summary: Direct evidence that the DDB2 complex displays ubiquitin-ligase activity (polyubiquitination), regulated by the COP9 signalosome. Reflects DDB2's substrate-receptor role in CRL4-mediated ubiquitination. Reason: Supported by the demonstration of ubiquitin ligase activity in the DDB2/CUL4A/Roc1 complex. Supporting Evidence: PMID:12732143 Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:12732143 The ubiquitin ligase activity in the DDB2 and CSA complexes ...	ACCEPT	Summary: Direct evidence that DDB2 contributes to the ubiquitin-transferase activity of the DDB2/CUL4A/Roc1 complex. DDB2 itself is the substrate receptor (not the catalytic RING), hence contributes_to is appropriate. Reason: Correct use of contributes_to; DDB2 is the substrate-recognition module conferring activity on the complex, with the catalytic RING provided by RBX1/ROC1. Supporting Evidence: PMID:12732143 Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity
GO:0005515 protein binding	IPI PMID:12732143 The ubiquitin ligase activity in the DDB2 and CSA complexes ...	KEEP AS NON CORE	Summary: Interaction with DDB1 (Q16531) in the DDB2/COP9 complex study. Bare protein binding is uninformative. Reason: Real DDB1 interaction but bare protein binding is uninformative; captured by complex membership. Supporting Evidence: PMID:12732143 DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1
GO:0009411 response to UV	IDA PMID:12732143 The ubiquitin ligase activity in the DDB2 and CSA complexes ...	ACCEPT	Summary: Direct evidence that DDB2 complex ubiquitin ligase activity is regulated in response to UV irradiation. Reflects DDB2's UV-response role. Reason: Core process; DDB2's ligase activity and lesion recognition are UV-responsive. Supporting Evidence: PMID:12732143 CSN differentially regulates ubiquitin ligase activity of the DDB2 and CSA complexes in response to UV irradiation
GO:0032991 protein-containing complex	IDA PMID:12732143 The ubiquitin ligase activity in the DDB2 and CSA complexes ...	KEEP AS NON CORE	Summary: Generic protein-containing complex membership (the DDB2/CUL4A/Roc1/COP9 complex). A parent of the specific CRL4(DDB2) complex annotations. Reason: Correct but generic; subsumed by the specific Cul4-RING E3 ligase complex annotations. Supporting Evidence: PMID:12732143 DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1
GO:0051865 protein autoubiquitination	IDA PMID:12732143 The ubiquitin ligase activity in the DDB2 and CSA complexes ...	ACCEPT	Summary: Direct evidence that DDB2 is autoubiquitinated by its associated CRL4 ligase, a hallmark of its UV-induced self-degradation that limits its residence on damaged chromatin. Monoubiquitination is compatible with damaged-DNA binding, whereas polyubiquitination abolishes binding and routes DDB2 to proteasomal degradation; XPC (aided by centrin-2) competitively suppresses this ubiquitination to allow repeated rounds of repair. Reason: Supported; CRL4(DDB2) ubiquitinates DDB2 itself, leading to its proteasomal degradation, an integral feature of the lesion-handoff mechanism. Supporting Evidence: PMID:33937266 DDB2 directly binds CPDs and subsequently undergoes ubiquitination and proteasomal degradation file:human/DDB2/DDB2-deep-research-falcon.md while unmodified DDB2 binds UV-damaged DNA, poly-ubiquitinated DDB2 is recovered predominantly unbound and poly-ubiquitination abrogates damaged-DNA binding, promoting proteasomal degradation after UV exposure.
GO:0006289 nucleotide-excision repair	TAS PMID:8407967 Characterization of a human DNA damage binding protein impli...	ACCEPT	Summary: Author statement (XP-E DNA damage binding protein characterization) of DDB2's role in nucleotide-excision repair. Core process. Reason: Core biological process; redundant with IDA/ISS evidence. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair
GO:0003677 DNA binding	TAS PMID:8798680 Mutations specific to the xeroderma pigmentosum group E Ddb-...	KEEP AS NON CORE	Summary: Author statement of DNA binding (XP-E mutations study). A parent of the specific damaged-DNA binding function. Reason: Correct but generic; the specific GO:0003684 (damaged DNA binding) better captures DDB2's selectivity for photolesions. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP)
GO:0003684 damaged DNA binding	TAS PMID:8407967 Characterization of a human DNA damage binding protein impli...	ACCEPT	Summary: Author statement of damaged-DNA binding for the XP-E DNA-damage-binding protein (DDB2). Core molecular function. Reason: Core molecular function; redundant with IDA/ISS/IBA evidence. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP)
GO:0006281 DNA repair	TAS PMID:8798680 Mutations specific to the xeroderma pigmentosum group E Ddb-...	KEEP AS NON CORE	Summary: Author statement of DDB2's involvement in DNA repair. A parent of the specific nucleotide-excision repair role. Reason: Correct but generic; the specific nucleotide-excision repair / GG-NER annotations better capture the core role. Supporting Evidence: file:human/DDB2/DDB2-uniprot.txt Protein, which is both involved in DNA repair and protein ubiquitination

Core Functions

Damage-sensing subunit of the UV-DDB (DDB1-DDB2) complex that directly binds UV-induced photolesions (CPDs and 6-4PPs) in chromatinized DNA and recruits/hands off the lesion to XPC to initiate global-genome nucleotide excision repair.

Molecular Function:

damaged DNA binding

Directly Involved In:

nucleotide-excision repair

Cellular Locations:

site of DNA damage chromatin

Supporting Evidence:

PMID:12944386
p48 activates the recruitment of XPC to CPDs and may be the initial recognition factor in the NER pathway
file:human/DDB2/DDB2-uniprot.txt
The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches

Substrate-recognition receptor (DCAF) of the CRL4(DDB2) (DDB1-CUL4A/CUL4B-RBX1) E3 ubiquitin ligase that assembles on UV-damaged chromatin and directs ubiquitination of histones (H2A, H3, H4), of XPC, and of DDB2 itself, helping remodel damaged nucleosomes and couple lesion recognition to repair.

Molecular Function:

ubiquitin-protein transferase activity

Directly Involved In:

protein polyubiquitination

Cellular Locations:

chromatin

In Complex:

Cul4-RING E3 ubiquitin ligase complex

Supporting Evidence:

PMID:16473935
DDB2, as the substrate receptor of the DDB1-CUL4A-based ligase, specifically targets histone H2A for monoubiquitination in a photolesion-binding-dependent manner
PMID:12732143
Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity

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:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

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

GO_REF:0000114

Manual transfer of experimentally-verified manual GO annotation data to homologous complexes by curator judgment of sequence, composition and function similarity

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11564863

Human STAGA complex is a chromatin-acetylating transcription coactivator that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo.

PMID:11705987

DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair.

PMID:12732143

The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage.

DDB2 is integrated via DDB1 into a CUL4A/Roc1 ubiquitin ligase complex that displays ubiquitin ligase activity, regulated by the COP9 signalosome in response to UV.

PMID:12944386

In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product.

DDB2 (p48) localizes to both CPDs and 6-4PPs in vivo and activates recruitment of XPC to CPDs, acting as the initial recognition factor in NER.

PMID:14751237

Human DDB2 splicing variants are dominant negative inhibitors of UV-damaged DNA repair.

Splice variants D1 and D2 act as dominant-negative inhibitors of UV-damaged DNA repair by disrupting DDB1-DDB2 complex formation and DDB1 nuclear import.

PMID:16473935

The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites.

DDB2 is the substrate receptor of the DDB1-CUL4A ligase that monoubiquitinates histone H2A at UV-damaged sites in a photolesion-binding-dependent manner; mutations in DDB2 underlie XP-E.

PMID:16949367

A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1.

DDB2 is one of 18 identified Ddb1- and Cul4-associated factors (DCAFs) that serve as substrate receptors of CUL4 E3 ligases.

PMID:17041588

CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation.

PMID:17360488

HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1.

PMID:18593899

The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A.

PMID:19109893

Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex.

Crystal structure of the DDB1-DDB2 complex on damaged DNA reveals the molecular basis of photolesion recognition.

PMID:19966799

A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery.

PMID:21145461

Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.

PMID:22039351

Regulation of nucleotide excision repair by UV-DDB: prioritization of damage recognition to internucleosomal DNA.

PMID:22118460

The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation.

Defines the architecture, targeting and activation of the CRL4(DDB2) ubiquitin ligase; DDB2 is the substrate receptor.

PMID:22822215

Damaged DNA induced UV-damaged DNA-binding protein (UV-DDB) dimerization and its roles in chromatinized DNA repair.

PMID:22334663

Monoubiquitinated histone H2A destabilizes photolesion-containing nucleosomes with concomitant release of UV-damaged DNA-binding protein E3 ligase.

Monoubiquitinated H2A destabilizes photolesion-containing nucleosomes and releases the UV-DDB E3 ligase, coupling histone ubiquitination to lesion handoff and repair.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:28514442

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

PMID:30945288

Inflammation-dependent overexpression of c-Myc enhances CRL4(DCAF4) E3 ligase activity and promotes ubiquitination of ST7 in colitis-associated cancer.

PMID:32789493

The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2.

SIRT6 promotes repair of UV-induced DNA damage by targeting DDB2; DDB2 localizes to chromosome/damaged chromatin after UV.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33937266

USP44 Stabilizes DDB2 to Facilitate Nucleotide Excision Repair and Prevent Tumors.

DDB2 directly binds CPDs, undergoes ubiquitination/proteasomal degradation, and must remain on damaged chromatin to recruit and hand off lesions to XPC; USP44 deubiquitinates DDB2 to prevent premature degradation.

PMID:33961781

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

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:8407967

Characterization of a human DNA damage binding protein implicated in xeroderma pigmentosum E.

Characterizes the human DNA damage binding protein implicated in XP-E, supporting damaged-DNA binding and a NER role.

PMID:8798680

Mutations specific to the xeroderma pigmentosum group E Ddb- phenotype.

PMID:9418871

DDB, a putative DNA repair protein, can function as a transcriptional partner of E2F1.

file:human/DDB2/DDB2-deep-research-falcon.md

Falcon deep research report for human DDB2

DDB2 has an N-terminal helix-loop-helix that associates with DDB1 and a seven-bladed WD40 beta-propeller that mediates DNA binding.

"Structural work defines an N-terminal **helix–loop–helix (HLH)** used for DDB1 association and a **7-bladed WD40 β-propeller** that mediates DNA binding, matching the WD-repeat family/domain expectations given in the prompt."
The DDB2 propeller contacts ~7 bp around the lesion and bends the DNA by ~40 degrees with local strand separation; the DDB1-DDB2 interface is large (~3900 square angstroms).

"DDB2 contacts ~7 bp around the lesion and induces an approximately **40° DNA kink** with local strand separation. The DDB1–DDB2 interface is large (reported ~**3900 Å²**), consistent with stable heterodimerization."
Polyubiquitination abrogates DDB2 damaged-DNA binding and promotes proteasomal degradation after UV, whereas unmodified DDB2 binds UV-damaged DNA.

"while unmodified DDB2 binds UV-damaged DNA, **poly-ubiquitinated DDB2** is recovered predominantly unbound and **poly-ubiquitination abrogates damaged-DNA binding**, promoting proteasomal degradation after UV exposure."
XPC competitively suppresses DDB2 ubiquitination (enhanced by centrin-2), stabilizing DDB2 so it can initiate multiple rounds of repair.

"XPC competitively suppresses DDB2 ubiquitination in vitro, and this protection is enhanced by **centrin-2**, supporting a model in which XPC enables DDB2 to initiate multiple rounds of repair by limiting DDB2 degradation."

Reactome:R-HSA-5689317

Formation of the pre-incision complex in GG-NER

Reactome:R-HSA-5689861

Recruitment of XPA and release of CAK

Reactome:R-HSA-5690213

DNA polymerases delta, epsilon or kappa bind the GG-NER site

Reactome:R-HSA-5690988

3'-incision of DNA by ERCC5 (XPG) in GG-NER

Reactome:R-HSA-5690990

5'- incision of DNA by ERCC1:ERCC4 in GG-NER

Reactome:R-HSA-5690991

Binding of ERCC1:ERCC4 (ERCC1:XPF) to pre-incision complex in GG-NER

Reactome:R-HSA-5690996

ERCC2 and ERCC3 DNA helicases form an open bubble structure in damaged DNA

Reactome:R-HSA-5691000

TFIIH binds GG-NER site to form a verification complex

Reactome:R-HSA-5691006

XPC:RAD23:CETN2 and UV-DDB bind distorted dsDNA site

Reactome:R-HSA-5696655

PARP1 or PARP2 PARylates DDB2 and autoPARylates

Reactome:R-HSA-5696664

PARP1 or PARP2 binds DDB2 at GG-NER site

Reactome:R-HSA-5696670

CHD1L is recruited to GG-NER site

Reactome:R-HSA-5696997

USP24 deubiquitinates DDB2

Reactome:R-HSA-6782943

UV-DDB ubiquitinates XPC

Reactome:R-HSA-6790454

SUMOylation of XPC

Reactome:R-HSA-6790487

RNF111 ubiquitinates SUMOylated XPC

Reactome:R-HSA-6806423

TP53 stimulates DDB2 expression

Reactome:R-HSA-8952638

AcM-UBE2M transfers NEDD8 to CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8952639

NEDD8:AcM-UBE2M binds CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8955245

CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus

Reactome:R-HSA-8955285

COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8956045

COP9 signalosome deneddylates nuclear CRL4 E3 ubiquitin ligase complex

Suggested Experiments

Experiment: Reconstitute CRL4(DDB2) on defined nucleosomes containing a single CPD or 6-4PP and measure, by quantitative mass spectrometry, the kinetics and lysine-site specificity of histone, XPC and DDB2 ubiquitination, dissecting the contributions of CUL4A vs CUL4B.

Experiment: Use live-cell imaging with separation-of-function DDB2 mutants (DNA-binding-competent but ligase-dead, or autoubiquitination-resistant) to quantify lesion residence time, XPC recruitment kinetics and GG-NER efficiency for CPDs vs 6-4PPs.

Experiment: Using in vitro damaged-DNA binding assays with DDB2 bearing defined mono- versus poly-ubiquitin chains, and titrating XPC and centrin-2, quantify how the ubiquitination state and XPC/centrin-2 occupancy switch DDB2 between lesion-bound and degradation-bound states.

Deep Research

Falcon

(DDB2-deep-research-falcon.md)

Comprehensive Research Report: Human **DDB2** (UniProt Q92466) Falcon Edison Scientific Literature 23 citations 1 artifacts 2026-06-13T07:06:34.759348

Edison artifact artifact-00 (text/markdown)

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

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

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

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

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

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

Comprehensive Research Report: Human DDB2 (UniProt Q92466)

1. Target verification (gene/protein identity)

The UniProt accession Q92466 corresponds to human DDB2 (DNA damage-binding protein 2; also called DDB p48 / UV-DDB2 / XPE/p48), a WD40-repeat protein that heterodimerizes with DDB1 to form UV-DDB and functions in DNA damage recognition. Structural work defines an N-terminal helix–loop–helix (HLH) used for DDB1 association and a 7-bladed WD40 β-propeller that mediates DNA binding, matching the WD-repeat family/domain expectations given in the prompt. (scrima2008structuralbasisof pages 2-3, jia2011bimodalmechanismof pages 20-24)

2. Key concepts and definitions (current understanding)

2.1 Global-genome nucleotide excision repair (GG-NER) damage recognition

A key initiating step of mammalian GG-NER is lesion detection in chromatin and recruitment of the canonical sensor XPC. DDB2, as part of the DDB1–DDB2 (UV-DDB) complex, functions as an early damage-recognition factor that binds UV photolesions and helps promote recruitment/“handoff” to XPC, particularly for lesions that XPC detects inefficiently. (matsumoto2015functionalregulationof pages 1-2, clement2010dynamictwostagemechanism pages 22-27, jia2011bimodalmechanismof pages 44-49)

2.2 UV-DDB and CRL4\^DDB2 ubiquitin signaling

DDB2 also acts as a substrate receptor within a cullin-RING E3 ubiquitin ligase CRL4\^DDB2 (CUL4–RBX1–DDB1–DDB2). Upon binding to UV-damaged chromatin, this ligase can ubiquitinate multiple proteins at damage sites (including DDB2 itself, XPC, and histones), coupling lesion recognition to ubiquitin signaling and chromatin remodeling during repair initiation. (matsumoto2015functionalregulationof pages 1-2)

3. Molecular function and mechanism (primary function)

3.1 DNA lesion binding and substrate/lesion specificity

Lesion types recognized. DDB2 is reported to recognize UV-induced lesions, including cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs), and it has been described to bind additional abnormal DNA structures including mismatches, apurinic/apyrimidinic (AP) sites, and compound lesions. (matsumoto2015functionalregulationof pages 12-13, jia2011bimodalmechanismof pages 20-24, clement2010dynamictwostagemechanism pages 22-27)

Structural basis of binding. Crystal structures of the human DDB1–DDB2 complex bound to damaged DNA (including a 6-4PP and an abasic site mimic, THF) show that DDB2’s WD40 β-propeller mediates DNA binding and recognition. DDB2 contacts ~7 bp around the lesion and induces an approximately 40° DNA kink with local strand separation. The DDB1–DDB2 interface is large (reported ~3900 Å²), consistent with stable heterodimerization. (Scrima et al., Cell, Dec 2008, https://doi.org/10.1016/j.cell.2008.10.045) (scrima2008structuralbasisof pages 2-3)

3.2 Role as a damage-recognition “organizer” and XPC recruitment/handoff

In chromatin, DDB2 rapidly translocates to UV lesions and associates with damaged chromatin ahead of XPC, consistent with a model where UV-DDB serves as an initial lesion sensor and organizer that facilitates subsequent XPC engagement. (jia2011bimodalmechanismof pages 20-24, jia2011bimodalmechanismof pages 44-49)

One mechanistic model emphasizes that DDB2 promotes GG-NER by both (i) ubiquitin-linked mechanisms that affect XPC behavior in chromatin and (ii) ubiquitin-independent transient interactions that help XPC productively engage lesions. (jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 44-49)

4. Regulation, localization, and pathway context

4.1 Subcellular localization

DDB2’s function is primarily nuclear, where it rapidly relocates to UV-damaged chromatin and binds lesions with high affinity relative to other NER factors, consistent with its role in early damage recognition in GG-NER. (jia2011bimodalmechanismof pages 20-24, jia2011bimodalmechanismof pages 44-49)

4.2 Ubiquitination and protein stability (a key regulatory circuit)

Poly-ubiquitination suppresses DNA binding and promotes turnover. Experimental work shows that while unmodified DDB2 binds UV-damaged DNA, poly-ubiquitinated DDB2 is recovered predominantly unbound and poly-ubiquitination abrogates damaged-DNA binding, promoting proteasomal degradation after UV exposure. (Matsumoto et al., Nucleic Acids Research, Jan 2015, https://doi.org/10.1093/nar/gkv038) (matsumoto2015functionalregulationof pages 5-7, matsumoto2015functionalregulationof pages 1-2)

XPC-dependent stabilization. Endogenous DDB2 can be stabilized after UV as a function of XPC expression: XPC competitively suppresses DDB2 ubiquitination in vitro, and this protection is enhanced by centrin-2, supporting a model in which XPC enables DDB2 to initiate multiple rounds of repair by limiting DDB2 degradation. (matsumoto2015functionalregulationof pages 1-2)

Additional regulatory nodes. Regulatory influences described in this framework include COP9 signalosome–linked control of CRL4 ligase activity, and other modulators (e.g., p38 MAPK and PARP1-dependent stabilization described in the same mechanistic context). (matsumoto2015functionalregulationof pages 12-13)

4.3 Chromatin context and quantitative repair-associated observations

A chromatin-centric model reported that ~90% of 6-4PPs occur in MNase-sensitive chromatin and ~75% of 6-4PPs are removed within the first hour in wild-type cells, with DDB2 loss (XP-E) associated with delayed early 6-4PP repair; XP-E contexts were described as having ~50% CPD excision efficiency in the cited model. (jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 20-24)

5. Recent developments and latest research (prioritizing 2023–2024)

5.1 DDB2 in radiotherapy and PARP inhibitor response (PDAC; 2024)

A 2024 study in pancreatic ductal adenocarcinoma (PDAC) cell lines (T3M4 and Capan-2) reported that higher DDB2 expression is associated with radioresistance, including fewer residual DNA damage markers after irradiation (γH2AX foci differences with reported p-values). The work proposes DDB2 as a predictive biomarker for radiotherapy response and suggests that low DDB2 expression may enhance radiosensitization by olaparib in certain PDAC contexts. (Dardare et al., Cell Death Discovery, Sep 2024, https://doi.org/10.1038/s41420-024-02188-9) (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-6)

Mechanistically, the same study links DDB2 to Chk1/Chk2 phosphorylation, G2/M arrest, and increased PARP1 expression/activity, connecting DDB2 to DNA damage response circuitry beyond canonical UV-lesion GG-NER. (dardare2024ddb2expressionlights pages 6-7, dardare2024ddb2expressionlights pages 6-6)

5.2 DDB2–PCNA interaction and EMT/NF-κB programs (2024)

A 2024 BMC Cancer study examined a DDB2 mutant defective in PCNA binding (DDB2\u2009PCNA−) in UV-damaged human cells and reported enhanced EMT-like changes and increased NF-κB pathway activity, including increased nuclear localization of NF-κB and altered EMT marker behavior. The study also reported a detectable DDB2–NF-κB interaction that was stronger with the PCNA-binding-deficient DDB2 mutant, implicating the DDB2–PCNA interaction in restraining EMT/NF-κB programs after UV damage in this model. (Perucca et al., BMC Cancer, May 2024, https://doi.org/10.1186/s12885-024-12368-6) (perucca2024epithelialtomesenchymaltransitionand pages 11-14, perucca2024epithelialtomesenchymaltransitionand pages 1-2)

6. Current applications and real-world implementations

6.1 Rapid biodosimetry after radiation exposure (FAST-DOSE; 2024)

A 2024 Scientific Reports study advanced DDB2 as a protein biomarker (with BAX) for acute radiation exposure using ELISA and machine-learning models in human and non-human primate (NHP) blood.

Exposure classification performance: median AUC ~0.9914 (human) and ~0.987 (NHP), with accuracy 97.92% (human) and 96% (NHP) for classifying irradiated vs unirradiated ex vivo samples up to 48 h post-exposure. (Kanagaraj et al., Scientific Reports, Aug 2024, https://doi.org/10.1038/s41598-024-69852-z) (kanagaraj2024baxandddb2 pages 6-7, kanagaraj2024baxandddb2 pages 3-6)
Dose reconstruction: human testing-set R²=0.7914, RMSE=0.8007 Gy, MAE=0.6304 Gy; NHP testing-set R²=0.7980, RMSE=0.7816 Gy, MAE=0.6099 Gy. (kanagaraj2024baxandddb2 pages 3-6)
Operational details: ex vivo dose range 0–5 Gy with readouts at ~24 h and ~48 h; an in vivo NHP cohort (n=4) received 2.5 Gy total-body irradiation with blood sampling on days 2, 5, and 14. (kanagaraj2024baxandddb2 pages 6-7, kanagaraj2024baxandddb2 pages 7-8)

These reported performance statistics support DDB2’s practical deployment in multi-marker biodosimetry pipelines and highlight a real-world implementation path distinct from DDB2’s original NER context. (kanagaraj2024baxandddb2 pages 1-2, kanagaraj2024baxandddb2 pages 3-6)

6.2 Oncology biomarker hypothesis generation (preclinical)

Recent PDAC findings position DDB2 expression as a candidate biomarker for stratifying radiotherapy response and potentially PARP-inhibitor radiosensitization strategies in preclinical PDAC models. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-6)

7. Synthesis and expert-style analysis (evidence-constrained)

Collectively, the strongest, most direct mechanistic evidence supports DDB2’s primary role as a WD40-repeat DNA lesion sensor in GG-NER, functioning through UV-DDB to recognize UV photolesions (notably 6-4PPs and CPDs) and to coordinate lesion processing by coupling detection to XPC recruitment/handoff and CRL4\^DDB2 ubiquitin signaling in chromatin. (scrima2008structuralbasisof pages 2-3, matsumoto2015functionalregulationof pages 1-2, clement2010dynamictwostagemechanism pages 22-27)

Recent 2024 studies extend DDB2’s translational relevance into (i) radiotherapy/PARP inhibitor response hypotheses in PDAC models and (ii) an applied biodosimetry setting where DDB2 protein levels contribute to high-accuracy classification and dose reconstruction. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-6, kanagaraj2024baxandddb2 pages 3-6)

8. Evidence summary table

The following table consolidates the evidence-backed functional annotation.

Category	Summary
Identity/domains	Human DDB2 is the DNA damage-binding protein 2 encoded by DDB2 (UniProt Q92466), a WD40-family protein that contains an N-terminal helix-loop-helix region for DDB1 association and a 7-bladed WD40 β-propeller that mediates DNA binding; DDB2 is unstable/poorly soluble without DDB1. (scrima2008structuralbasisof pages 2-3, jia2011bimodalmechanismof pages 20-24)
Core molecular function	DDB2 is the lesion-recognition subunit of the UV-DDB complex and acts early in global-genome nucleotide excision repair (GG-NER) by binding UV-damaged DNA and facilitating recruitment/transfer to XPC, especially for lesions that XPC recognizes inefficiently on its own. (matsumoto2015functionalregulationof pages 1-2, clement2010dynamictwostagemechanism pages 22-27, jia2011bimodalmechanismof pages 44-49)
Lesion specificity	DDB2 binds strongly to UV photolesions, particularly 6-4 photoproducts and also CPDs; reported substrates additionally include abasic/AP sites, mismatches, and compound lesions. Structural work showed recognition of a 6-4PP and an abasic-site mimic (THF). (scrima2008structuralbasisof pages 2-3, matsumoto2015functionalregulationof pages 12-13, jia2011bimodalmechanismof pages 20-24, clement2010dynamictwostagemechanism pages 22-27)
Key complexes/partners	DDB2 forms a heterodimer with DDB1 (UV-DDB) and serves as the substrate receptor in the CRL4^DDB2 ubiquitin ligase with CUL4A/RBX1; functionally important partners include XPC, centrin-2, COP9 signalosome, PARP1, p97 segregase, and chromatin substrates such as histones. (scrima2008structuralbasisof pages 2-3, matsumoto2015functionalregulationof pages 12-13, matsumoto2015functionalregulationof pages 5-7, matsumoto2015functionalregulationof pages 1-2)
Post-translational regulation	UV-damage binding activates CRL4^DDB2-dependent ubiquitination of DDB2, XPC, and histones; mono-ubiquitination can be compatible with damage binding, whereas poly-ubiquitination abrogates DDB2 damaged-DNA binding and promotes proteasomal degradation. XPC competitively suppresses DDB2 ubiquitination and stabilizes endogenous DDB2 after UV; regulation also involves COP9/neddylation, p38 MAPK, and PARP1-mediated stabilization. (matsumoto2015functionalregulationof pages 12-13, matsumoto2015functionalregulationof pages 5-7, matsumoto2015functionalregulationof pages 1-2)
Cellular localization	DDB2 functions primarily in the nucleus on UV-damaged chromatin, where it rapidly translocates after UV exposure, binds lesions ahead of XPC, and accumulates at chromatin-associated repair sites. (jia2011bimodalmechanismof pages 20-24, jia2011bimodalmechanismof pages 44-49)
Pathways	DDB2 operates in global-genome NER, coupling lesion detection to chromatin remodeling and ubiquitin signaling; its activity promotes lesion handoff to XPC and helps organize repair in accessible chromatin regions. Recent PDAC work also links DDB2 to ionizing-radiation responses via checkpoint signaling and PARP1-associated DSB repair processes. (jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 44-49, dardare2024ddb2expressionlights pages 6-7, dardare2024ddb2expressionlights pages 6-6)
2023-2024 developments	Recent studies expand DDB2 biology beyond canonical UV repair: in PDAC, higher DDB2 promoted radioresistance, Chk1/Chk2 phosphorylation, PARP1 activity, and reduced residual γH2AX after irradiation; in tumor-biology models, reduced or altered DDB2 regulation was linked to EMT/NF-κB programs and metastasis-associated phenotypes. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-7, perucca2024epithelialtomesenchymaltransitionand pages 11-14, perucca2024epithelialtomesenchymaltransitionand pages 1-2, perucca2024epithelialtomesenchymaltransitionand pages 14-15)
Applications/biomarkers	DDB2 is being investigated as a predictive biomarker for radiotherapy response and olaparib radiosensitization in PDAC, and as a protein biomarker in radiation biodosimetry assays; recent cancer studies also support its relevance as a metastasis/EMT-associated regulatory node in some tumor contexts. (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-7)
Quantitative stats	Structural studies reported DDB2-induced ~40° DNA kinking, ~2100 Å² DNA-contact surface, and ~3900 Å² DDB1-DDB2 interface; one mechanistic model reported ~90% of 6-4PPs in MNase-sensitive chromatin and ~75% removed within 1 h in wild-type cells, with ~50% CPD excision efficiency in XP-E settings. In a 2024 biodosimetry assay using DDB2+BAX, classification accuracy was 97.92% in human and 96% in NHP blood, with dose-prediction R² values of 0.79 and 0.80, respectively. (scrima2008structuralbasisof pages 2-3, jia2011bimodalmechanismof pages 122-126, jia2011bimodalmechanismof pages 20-24)

Table: This table summarizes the evidence-backed functional annotation of human DDB2 (UniProt Q92466), covering its identity, molecular role in GG-NER, regulation, recent 2023-2024 developments, and emerging biomarker applications. It is useful as a compact reference linking each claim to specific retrieved evidence contexts.

Key primary sources used (with dates and URLs)

Scrima A. et al. “Structural Basis of UV DNA-Damage Recognition by the DDB1–DDB2 Complex.” Cell (Dec 2008). https://doi.org/10.1016/j.cell.2008.10.045 (scrima2008structuralbasisof pages 2-3)
Matsumoto S. et al. “Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein.” Nucleic Acids Research (Jan 2015). https://doi.org/10.1093/nar/gkv038 (matsumoto2015functionalregulationof pages 1-2, matsumoto2015functionalregulationof pages 5-7)
Dardare J. et al. “DDB2 expression lights the way for precision radiotherapy response in PDAC cells, with or without olaparib.” Cell Death Discovery (Sep 2024). https://doi.org/10.1038/s41420-024-02188-9 (dardare2024ddb2expressionlights pages 1-2, dardare2024ddb2expressionlights pages 6-6)
Perucca P. et al. “Epithelial-to-mesenchymal transition and NF-kB pathways are promoted by a mutant form of DDB2, unable to bind PCNA, in UV-damaged human cells.” BMC Cancer (May 2024). https://doi.org/10.1186/s12885-024-12368-6 (perucca2024epithelialtomesenchymaltransitionand pages 11-14, perucca2024epithelialtomesenchymaltransitionand pages 1-2)
Kanagaraj K. et al. “BAX and DDB2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models.” Scientific Reports (Aug 2024). https://doi.org/10.1038/s41598-024-69852-z (kanagaraj2024baxandddb2 pages 3-6, kanagaraj2024baxandddb2 pages 7-8)

References

(scrima2008structuralbasisof pages 2-3): Andrea Scrima, Renata Koníčková, Bryan K. Czyzewski, Yusuke Kawasaki, Philip D. Jeffrey, Regina Groisman, Yoshihiro Nakatani, Shigenori Iwai, Nikola P. Pavletich, and Nicolas H. Thomä. Structural basis of uv dna-damage recognition by the ddb1–ddb2 complex. Cell, 135:1213-1223, Dec 2008. URL: https://doi.org/10.1016/j.cell.2008.10.045, doi:10.1016/j.cell.2008.10.045. This article has 546 citations and is from a highest quality peer-reviewed journal.
(jia2011bimodalmechanismof pages 20-24): Jia Fei. Bimodal mechanism of dna repair stimulation by ddb2 (xpe) in chromatin. ArXiv, 2011. URL: https://doi.org/10.5167/uzh-164006, doi:10.5167/uzh-164006. This article has 0 citations.
(matsumoto2015functionalregulationof pages 1-2): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thomä, and Kaoru Sugasawa. Functional regulation of the dna damage-recognition factor ddb2 by ubiquitination and interaction with xeroderma pigmentosum group c protein. Nucleic Acids Research, 43:1700-1713, Jan 2015. URL: https://doi.org/10.1093/nar/gkv038, doi:10.1093/nar/gkv038. This article has 69 citations and is from a highest quality peer-reviewed journal.
(clement2010dynamictwostagemechanism pages 22-27): Flurina C. Clement, Ulrike Camenisch, Jia Fei, Nina Kaczmarek, Nadine Mathieu, and Hanspeter Naegeli. Dynamic two-stage mechanism of versatile dna damage recognition by xeroderma pigmentosum group c protein. Mutation research, 685 1-2:21-8, Mar 2010. URL: https://doi.org/10.1016/j.mrfmmm.2009.08.005, doi:10.1016/j.mrfmmm.2009.08.005. This article has 56 citations and is from a peer-reviewed journal.
(jia2011bimodalmechanismof pages 44-49): Jia Fei. Bimodal mechanism of dna repair stimulation by ddb2 (xpe) in chromatin. ArXiv, 2011. URL: https://doi.org/10.5167/uzh-164006, doi:10.5167/uzh-164006. This article has 0 citations.
(matsumoto2015functionalregulationof pages 12-13): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thomä, and Kaoru Sugasawa. Functional regulation of the dna damage-recognition factor ddb2 by ubiquitination and interaction with xeroderma pigmentosum group c protein. Nucleic Acids Research, 43:1700-1713, Jan 2015. URL: https://doi.org/10.1093/nar/gkv038, doi:10.1093/nar/gkv038. This article has 69 citations and is from a highest quality peer-reviewed journal.
(jia2011bimodalmechanismof pages 122-126): Jia Fei. Bimodal mechanism of dna repair stimulation by ddb2 (xpe) in chromatin. ArXiv, 2011. URL: https://doi.org/10.5167/uzh-164006, doi:10.5167/uzh-164006. This article has 0 citations.
(matsumoto2015functionalregulationof pages 5-7): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thomä, and Kaoru Sugasawa. Functional regulation of the dna damage-recognition factor ddb2 by ubiquitination and interaction with xeroderma pigmentosum group c protein. Nucleic Acids Research, 43:1700-1713, Jan 2015. URL: https://doi.org/10.1093/nar/gkv038, doi:10.1093/nar/gkv038. This article has 69 citations and is from a highest quality peer-reviewed journal.
(dardare2024ddb2expressionlights pages 1-2): Julie Dardare, Andréa Witz, Margaux Betz, Aurélie François, Laureline Lamy, Marie Husson, Jessica Demange, Marie Rouyer, Aurélien Lambert, Jean-Louis Merlin, Pauline Gilson, and Alexandre Harlé. Ddb2 expression lights the way for precision radiotherapy response in pdac cells, with or without olaparib. Cell Death Discovery, Sep 2024. URL: https://doi.org/10.1038/s41420-024-02188-9, doi:10.1038/s41420-024-02188-9. This article has 10 citations and is from a peer-reviewed journal.
(dardare2024ddb2expressionlights pages 6-6): Julie Dardare, Andréa Witz, Margaux Betz, Aurélie François, Laureline Lamy, Marie Husson, Jessica Demange, Marie Rouyer, Aurélien Lambert, Jean-Louis Merlin, Pauline Gilson, and Alexandre Harlé. Ddb2 expression lights the way for precision radiotherapy response in pdac cells, with or without olaparib. Cell Death Discovery, Sep 2024. URL: https://doi.org/10.1038/s41420-024-02188-9, doi:10.1038/s41420-024-02188-9. This article has 10 citations and is from a peer-reviewed journal.
(dardare2024ddb2expressionlights pages 6-7): Julie Dardare, Andréa Witz, Margaux Betz, Aurélie François, Laureline Lamy, Marie Husson, Jessica Demange, Marie Rouyer, Aurélien Lambert, Jean-Louis Merlin, Pauline Gilson, and Alexandre Harlé. Ddb2 expression lights the way for precision radiotherapy response in pdac cells, with or without olaparib. Cell Death Discovery, Sep 2024. URL: https://doi.org/10.1038/s41420-024-02188-9, doi:10.1038/s41420-024-02188-9. This article has 10 citations and is from a peer-reviewed journal.
(perucca2024epithelialtomesenchymaltransitionand pages 11-14): Paola Perucca, Elisabetta Bassi, Martina Vetro, Anna Tricarico, Ennio Prosperi, Lucia Anna Stivala, and Ornella Cazzalini. Epithelial-to-mesenchymal transition and nf-kb pathways are promoted by a mutant form of ddb2, unable to bind pcna, in uv-damaged human cells. BMC Cancer, May 2024. URL: https://doi.org/10.1186/s12885-024-12368-6, doi:10.1186/s12885-024-12368-6. This article has 5 citations and is from a peer-reviewed journal.
(perucca2024epithelialtomesenchymaltransitionand pages 1-2): Paola Perucca, Elisabetta Bassi, Martina Vetro, Anna Tricarico, Ennio Prosperi, Lucia Anna Stivala, and Ornella Cazzalini. Epithelial-to-mesenchymal transition and nf-kb pathways are promoted by a mutant form of ddb2, unable to bind pcna, in uv-damaged human cells. BMC Cancer, May 2024. URL: https://doi.org/10.1186/s12885-024-12368-6, doi:10.1186/s12885-024-12368-6. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 6-7): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 3-6): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 7-8): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(kanagaraj2024baxandddb2 pages 1-2): Karthik Kanagaraj, Michelle A. Phillippi, Elizabeth H. Ober, Igor Shuryak, Norman J. Kleiman, John Olson, George Schaaf, J. Mark Cline, and Helen C. Turner. Bax and ddb2 as biomarkers for acute radiation exposure in the human blood ex vivo and non-human primate models. Scientific Reports, Aug 2024. URL: https://doi.org/10.1038/s41598-024-69852-z, doi:10.1038/s41598-024-69852-z. This article has 5 citations and is from a peer-reviewed journal.
(perucca2024epithelialtomesenchymaltransitionand pages 14-15): Paola Perucca, Elisabetta Bassi, Martina Vetro, Anna Tricarico, Ennio Prosperi, Lucia Anna Stivala, and Ornella Cazzalini. Epithelial-to-mesenchymal transition and nf-kb pathways are promoted by a mutant form of ddb2, unable to bind pcna, in uv-damaged human cells. BMC Cancer, May 2024. URL: https://doi.org/10.1186/s12885-024-12368-6, doi:10.1186/s12885-024-12368-6. This article has 5 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

matsumoto2015functionalregulationof pages 1-2
scrima2008structuralbasisof pages 2-3
matsumoto2015functionalregulationof pages 12-13
jia2011bimodalmechanismof pages 20-24
clement2010dynamictwostagemechanism pages 22-27
jia2011bimodalmechanismof pages 44-49
jia2011bimodalmechanismof pages 122-126
matsumoto2015functionalregulationof pages 5-7
perucca2024epithelialtomesenchymaltransitionand pages 11-14
perucca2024epithelialtomesenchymaltransitionand pages 1-2
perucca2024epithelialtomesenchymaltransitionand pages 14-15
https://doi.org/10.1016/j.cell.2008.10.045
https://doi.org/10.1093/nar/gkv038
https://doi.org/10.1038/s41420-024-02188-9
https://doi.org/10.1186/s12885-024-12368-6
https://doi.org/10.1038/s41598-024-69852-z
https://doi.org/10.1016/j.cell.2008.10.045,
https://doi.org/10.5167/uzh-164006,
https://doi.org/10.1093/nar/gkv038,
https://doi.org/10.1016/j.mrfmmm.2009.08.005,
https://doi.org/10.1038/s41420-024-02188-9,
https://doi.org/10.1186/s12885-024-12368-6,
https://doi.org/10.1038/s41598-024-69852-z,

📚 Additional Documentation

Pn Notes

(DDB2-pn-notes.md)

DDB2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q92466
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/DDB2/DDB2-ai-review.yaml
AIGR review HTML: missing - genes/human/DDB2/DDB2-ai-review.html
Gene notes: missing - genes/human/DDB2/DDB2-notes.md
GOA TSV: present - genes/human/DDB2/DDB2-goa.tsv
UniProt record: present - genes/human/DDB2/DDB2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/DDB2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/DDB2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/DDB2/DDB2-deep-research-falcon.md

AIGR Review Snapshot

Description: DDB2 (DNA damage-binding protein 2, the p48 subunit of UV-DDB; XPE factor) is a nuclear protein built from an N-terminal helix-loop-helix that docks onto DDB1 and a seven-bladed WD40 beta-propeller that engages DNA. With DDB1 it forms the UV-damaged DNA-binding (UV-DDB) heterodimer, the UV-lesion sensor of global-genome nucleotide excision repair (GG-NER), which directly recognizes UV-induced photolesions, preferentially cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs), as well as apurinic/abasic (AP) sites and short mismatches. The propeller flips the damaged bases into a binding pocket and kinks the duplex by roughly 40 degrees with local strand separation. By binding CPDs that are otherwise poorly recognized, DDB2 recruits and hands off the lesion to the XPC-RAD23B complex to initiate downstream NER. DDB2 also acts as the substrate-recognition receptor (a DCAF) of a CUL4-RING E3 ubiquitin ligase, CRL4(DDB2) (DDB1-CUL4A/CUL4B-RBX1), assembling on chromatin at sites of UV damage. This ligase ubiquitinates chromatin histones (notably H2A, and H3/H4), ubiquitinates XPC to modulate its DNA binding, and autoubiquitinates DDB2 itself to trigger its turnover; these ubiquitination events help remodel and open damaged nucleosomes and hand the lesion to XPC. DDB2 activity is tightly coupled to its modification state: monoubiquitination is compatible with damage binding, whereas polyubiquitination abolishes damaged-DNA binding and promotes proteasomal degradation, and XPC (assisted by centrin-2) competitively suppresses DDB2 ubiquitination to stabilize it for repeated rounds of repair. The ligase is regulated by NEDD8 conjugation and by the COP9 signalosome, and DDB2 protein levels are controlled by ubiquitination/deubiquitination (e.g., USP24, USP44), by PARP1-dependent stabilization, and by p53, which induces DDB2 expression. Loss-of-function mutations in DDB2 cause xeroderma pigmentosum complementation group E (XP-E), with UV sensitivity and skin-cancer predisposition.
Existing/core annotation action counts: ACCEPT: 55; KEEP_AS_NON_CORE: 26

PN Consistency Summary

Consistency: Consistent on the substrate-receptor (DCAF) identity. Deep research, review and PN all describe DDB2 as the WD40 substrate-recognition receptor of CRL4(DDB2), plus the UV-DDB lesion sensor. Minor divergence in MF choice (see below). No biological contradiction.
PN story / NEW pressure: PN projects GO:1990756 (substrate-adaptor MF) as new_to_goa — and indeed GOA has no GO:1990756 (it has GO:0004842 contributes_to and GO:0003684 damaged-DNA binding; confirmed in goa.tsv). GO:1990756 is real (OLS) and biologically appropriate for DDB2 as a DCAF receptor. Verdict: ADD is defensible. The review instead represents the receptor MF as GO:0004842 (ubiquitin-protein transferase, contributes_to) and the sensor MF as GO:0003684; it does NOT propose GO:1990756.
Evidence alignment: PN row lists no references; the review is richly evidenced (PMID:12732143 ligase activity IDA; 16473935 H2A ubiquitination; 22334663 CUL4B complex; 19109893 UV-DDB structure; etc.), all marked VERIFIED. No conflict; PN simply under-cites.
Verdict: Consistent; PN GO:1990756 (receptor) is correctly categorized and a defensible add. Recommended edits: [YAML] consider adding GO:1990756 to DDB2 as the explicit DCAF substrate-receptor MF (complements existing GO:0004842 contributes_to), aligning with the PN projection.

Full Consistency Review

UniProt: Q92466 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor|WD40|other ; PN-node mapping: group "Cul4A/Cul4B substrate receptor"=mapped, ok_for_propagation, GO:1990756 (substrate-adaptor MF); subtype/type=no_mapping; projected GO:1990756 goa_status=new_to_goa.
Consistency: Consistent on the substrate-receptor (DCAF) identity. Deep research, review and PN all describe DDB2 as the WD40 substrate-recognition receptor of CRL4(DDB2), plus the UV-DDB lesion sensor. Minor divergence in MF choice (see below). No biological contradiction.
PN story / NEW pressure: PN projects GO:1990756 (substrate-adaptor MF) as new_to_goa — and indeed GOA has no GO:1990756 (it has GO:0004842 contributes_to and GO:0003684 damaged-DNA binding; confirmed in goa.tsv). GO:1990756 is real (OLS) and biologically appropriate for DDB2 as a DCAF receptor. Verdict: ADD is defensible. The review instead represents the receptor MF as GO:0004842 (ubiquitin-protein transferase, contributes_to) and the sensor MF as GO:0003684; it does NOT propose GO:1990756.
Mapping strategy: Correct category (substrate receptor → GO:1990756), unlike DDB1. DDB2 is genuinely the DCAF receptor of CRL4(DDB2), so GO:1990756 is well placed and narrower than the generic existing terms. Node status/scope fine.
Evidence alignment: PN row lists no references; the review is richly evidenced (PMID:12732143 ligase activity IDA; 16473935 H2A ubiquitination; 22334663 CUL4B complex; 19109893 UV-DDB structure; etc.), all marked VERIFIED. No conflict; PN simply under-cites.
Verdict: Consistent; PN GO:1990756 (receptor) is correctly categorized and a defensible add. Recommended edits: [YAML] consider adding GO:1990756 to DDB2 as the explicit DCAF substrate-receptor MF (complements existing GO:0004842 contributes_to), aligning with the PN projection.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/DDB2/DDB2-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul4A/Cul4B substrate receptor | WD40 | other

UniProt: Q92466
In branches: UPS
Signature domains: (none)
Auxiliary domains: IPR001680
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor|WD40|other
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor|WD40
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q92466
gene_symbol: DDB2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DDB2 (DNA damage-binding protein 2, the p48 subunit of UV-DDB; XPE factor) is a
  nuclear protein built from an N-terminal helix-loop-helix that docks onto DDB1
  and a seven-bladed WD40 beta-propeller that engages DNA. With DDB1 it forms the
  UV-damaged DNA-binding (UV-DDB) heterodimer, the UV-lesion sensor of
  global-genome nucleotide excision repair (GG-NER), which directly recognizes
  UV-induced photolesions, preferentially cyclobutane pyrimidine dimers (CPDs) and
  6-4 photoproducts (6-4PPs), as well as apurinic/abasic (AP) sites and short
  mismatches. The propeller flips the damaged bases into a binding pocket and
  kinks the duplex by roughly 40 degrees with local strand separation. By binding
  CPDs that are otherwise poorly recognized, DDB2 recruits and hands off the lesion
  to the XPC-RAD23B complex to initiate downstream NER. DDB2 also acts as the
  substrate-recognition receptor (a DCAF) of a CUL4-RING E3 ubiquitin ligase,
  CRL4(DDB2) (DDB1-CUL4A/CUL4B-RBX1), assembling on chromatin at sites of UV
  damage. This ligase ubiquitinates chromatin histones (notably H2A, and H3/H4),
  ubiquitinates XPC to modulate its DNA binding, and autoubiquitinates DDB2 itself
  to trigger its turnover; these ubiquitination events help remodel and open
  damaged nucleosomes and hand the lesion to XPC. DDB2 activity is tightly coupled
  to its modification state: monoubiquitination is compatible with damage binding,
  whereas polyubiquitination abolishes damaged-DNA binding and promotes
  proteasomal degradation, and XPC (assisted by centrin-2) competitively
  suppresses DDB2 ubiquitination to stabilize it for repeated rounds of repair.
  The ligase is regulated by NEDD8 conjugation and by the COP9 signalosome, and
  DDB2 protein levels are controlled by ubiquitination/deubiquitination (e.g.,
  USP24, USP44), by PARP1-dependent stabilization, and by p53, which induces DDB2
  expression. Loss-of-function mutations in DDB2 cause xeroderma
  pigmentosum complementation group E (XP-E), with UV sensitivity and skin-cancer
  predisposition.
alternative_products:
- name: '1'
  id: Q92466-1
- name: D1
  id: Q92466-2
  sequence_note: VSP_014675
- name: D2
  id: Q92466-3
  sequence_note: VSP_014676, VSP_014677
- name: D3
  id: Q92466-4
  sequence_note: VSP_014674
- name: D4
  id: Q92466-5
  sequence_note: VSP_014678, VSP_014679
existing_annotations:
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: contributes_to
  review:
    summary: Phylogenetic assignment of damaged-DNA binding, the core molecular function of DDB2 as the UV-lesion sensor of the UV-DDB complex.
    action: ACCEPT
    reason: Core molecular function, directly supported experimentally (UV-DDB binds CPDs/6-4PPs) and conserved across orthologs. Structural work shows the WD40 propeller flips the damaged bases out and kinks the duplex by ~40 degrees, the structural basis of lesion recognition.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway
    - reference_id: file:human/DDB2/DDB2-deep-research-falcon.md
      supporting_text: DDB2 contacts ~7 bp around the lesion and induces an approximately **40° DNA kink** with local strand separation. The DDB1–DDB2 interface is large (reported ~**3900 Å²**), consistent with stable heterodimerization.
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of damaged-DNA binding, redundant with the experimentally supported core function.
    action: ACCEPT
    reason: Correct core molecular function; redundant with IDA/IBA/TAS evidence.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of nuclear localization, the core compartment for DDB2's DNA-repair function.
    action: ACCEPT
    reason: Correct core localization; redundant with multiple EXP/IDA annotations.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of chromosome localization from the UniProt subcellular location; DDB2 accumulates on damaged chromatin/chromosomes after UV.
    action: ACCEPT
    reason: Correct localization; DDB2 acts on chromatinized DNA at damage sites; redundant with the EXP chromosome annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Chromosome {ECO:0000269|PubMed:32789493}. Note=Accumulates at sites of DNA damage following UV irradiation.
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic assignment of the general DNA repair process, a parent of the specific nucleotide-excision repair role of DDB2.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0006289 (nucleotide-excision repair) / GG-NER better captures the core role.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Protein, which is both involved in DNA repair and protein ubiquitination
- term:
    id: GO:0034644
    label: cellular response to UV
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of cellular response to UV, consistent with DDB2's role as the UV-lesion sensor.
    action: ACCEPT
    reason: Correct core process; DDB2 senses UV photolesions and initiates the response; redundant with EXP/ISS evidence.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: a complex that recognizes UV-induced DNA damage
- term:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: InterPro-based assignment of DDB2 as part of a CUL4-RING E3 ubiquitin ligase complex (CRL4(DDB2)), its core substrate-receptor context.
    action: ACCEPT
    reason: Core complex membership; DDB2 is the substrate-recognition (DCAF) module of CRL4(DDB2); redundant with EXP/IMP evidence.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Also functions as the substrate recognition module for the DCX (DDB2-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16473935
  qualifier: enables
  review:
    summary: IntAct interactions with DDB1 (Q16531) and CUL4A (Q13619) from the XP-E/H2A study, reflecting CRL4(DDB2) assembly. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real, functionally important complex partners (DDB1, CUL4A) but the bare protein binding term is uninformative per curation guidelines; captured by the complex part_of annotations.
    supported_by:
    - reference_id: PMID:16473935
      supporting_text: The UV-DDB complex is a component of the newly identified cullin 4A-based ubiquitin E3 ligase, DDB1-CUL4A(DDB2)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17041588
  qualifier: enables
  review:
    summary: Interactions with DDB1 and CUL4A from a study of CUL4-DDB1 WD40-repeat partners. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real complex interactions but bare protein binding is uninformative; captured by complex part_of annotations.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17360488
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) captured in a study of HIV-1 Vpr/DDB1. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real DDB1 interaction but bare protein binding is uninformative; the DDB1 association is captured by complex membership.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Component of the UV-DDB complex which includes DDB1 and DDB2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19109893
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) from the UV-DDB crystal-structure study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real DDB1 interaction underpinning the structural basis of damage recognition, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Component of the UV-DDB complex which includes DDB1 and DDB2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19966799
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) from a study of the helical motif anchoring DCAFs/viral hijackers to CUL4-DDB1. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real DDB1 interaction relevant to DCAF anchoring, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: DDB2 may function as the substrate recognition module within this complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21145461
  qualifier: enables
  review:
    summary: Interaction with CUL4A (Q13619) from a quantitative proteomics study of the CRL network. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real CRL network interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22039351
  qualifier: enables
  review:
    summary: Interactions with XPC (Q01831-1) and DDB1 (Q16531) from a study of UV-DDB prioritization of internucleosomal damage recognition. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful DDB2-XPC handoff interaction and DDB1 binding, but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:22039351
      supporting_text: UV-DDB
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22822215
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) from the UV-DDB dimerization study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real DDB1 interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Component of the UV-DDB complex which includes DDB1 and DDB2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Interaction with CUL4A (Q13619) from a quantitative interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput CRL interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Interactions with DDB1 and CUL4A from a large-scale interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30945288
  qualifier: enables
  review:
    summary: Interaction with CUL4A (Q13619) captured in a CRL4(DCAF4) study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput/CRL-context interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Interaction (P40337-2, VHL isoform) from a neurodegeneration interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Protein, which is both involved in DNA repair and protein ubiquitination
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Interactions with DDB1, CUL4A and others from a cell-specific interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) from the OpenCell endogenous-tagging interactome. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Component of the UV-DDB complex which includes DDB1 and DDB2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Interaction with CUL4A (Q13619) from a multimodal cell-map interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9418871
  qualifier: enables
  review:
    summary: Interaction with E2F1 (Q01094) and DDB1 (Q16531) reported in a study of DDB as a transcriptional partner of E2F1. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction (E2F1) supporting a peripheral transcriptional-partner role, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Protein, which is both involved in DNA repair and protein ubiquitination
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived general protein-ubiquitination process, a parent of the specific CRL4(DDB2)-mediated ubiquitination of histones/XPC.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the substrate-receptor role within CRL4(DDB2) and specific histone/XPC ubiquitination better capture the function.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:14751237
  qualifier: located_in
  review:
    summary: Direct (ComplexPortal-curated) nuclear localization of DDB2. Core compartment.
    action: ACCEPT
    reason: Core localization with direct support; DDB2 acts in the nucleus on damaged chromatin.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: NAS
  original_reference_id: PMID:22118460
  qualifier: located_in
  review:
    summary: Non-traceable author statement of nuclear localization, consistent with DDB2's core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with multiple experimental annotations.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: ISS
  original_reference_id: GO_REF:0000114
  qualifier: involved_in
  review:
    summary: Sequence/complex-similarity transfer of DNA damage response to the UV-DDB complex (CPX-477). A parent process of DDB2's specific UV-lesion-recognition role.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic relative to the specific GG-NER / cellular response to UV roles.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: a complex that recognizes UV-induced DNA damage
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: EXP
  original_reference_id: PMID:22118460
  qualifier: involved_in
  review:
    summary: Experimental (ComplexPortal) annotation of DNA damage response for CRL4(DDB2). A parent process of DDB2's specific UV-lesion role.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific nucleotide-excision repair / cellular response to UV annotations better capture the core role.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: EXP
  original_reference_id: PMID:22118460
  qualifier: part_of
  review:
    summary: Experimental membership of DDB2 in the CUL4A-RING (CRL4A(DDB2)) ligase complex, its core substrate-receptor context.
    action: ACCEPT
    reason: Core complex membership with experimental support; DDB2 is the DCAF substrate receptor of CRL4A.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: the DCX (DDB2-CUL4-X-box) E3 ubiquitin-protein ligase complex DDB2-CUL4-ROC1
- term:
    id: GO:0034644
    label: cellular response to UV
  evidence_type: ISS
  original_reference_id: GO_REF:0000114
  qualifier: involved_in
  review:
    summary: Complex-similarity transfer of cellular response to UV. Consistent with DDB2's UV-lesion-sensing role.
    action: ACCEPT
    reason: Correct core process; redundant with EXP evidence.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: a complex that recognizes UV-induced DNA damage
- term:
    id: GO:0034644
    label: cellular response to UV
  evidence_type: EXP
  original_reference_id: PMID:22118460
  qualifier: involved_in
  review:
    summary: Experimental annotation of cellular response to UV for CRL4(DDB2), reflecting DDB2's role as the UV-lesion sensor.
    action: ACCEPT
    reason: Core process with experimental support.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: a complex that recognizes UV-induced DNA damage
- term:
    id: GO:0070914
    label: UV-damage excision repair
  evidence_type: IDA
  original_reference_id: PMID:14751237
  qualifier: involved_in
  review:
    summary: Direct evidence that DDB2 functions in UV-damaged DNA repair; splice variants D1/D2 act as dominant-negative inhibitors of this process.
    action: ACCEPT
    reason: Core biological process; the dominant-negative variants demonstrate DDB2's requirement for UV-damage repair.
    supported_by:
    - reference_id: PMID:14751237
      supporting_text: D1 and D2 are dominant negative inhibitors of DNA repair
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for nucleoplasmic localization, consistent with DDB2's nuclear site of action.
    action: ACCEPT
    reason: Correct localization with IDA support; consistent with the core nuclear/chromatin compartment.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:11705987
  qualifier: located_in
  review:
    summary: Experimental evidence that DDB accumulates in the nucleus at DNA damage sites after UV. Core compartment.
    action: ACCEPT
    reason: Core localization with experimental support.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:12944386
  qualifier: located_in
  review:
    summary: Experimental nuclear localization of the DDB2 (p48) gene product at UV-irradiated sites. Core compartment.
    action: ACCEPT
    reason: Core localization with experimental support.
    supported_by:
    - reference_id: PMID:12944386
      supporting_text: p48 localized to UV-irradiated sites that contained either CPDs or 6-4PPs
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:16473935
  qualifier: located_in
  review:
    summary: Experimental nuclear localization within the XP-E/H2A ubiquitination study. Core compartment.
    action: ACCEPT
    reason: Core localization with experimental support.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:18593899
  qualifier: located_in
  review:
    summary: Experimental nuclear localization within the CUL4B-based UV-DDB ligase / H2A ubiquitination study. Core compartment.
    action: ACCEPT
    reason: Core localization with experimental support.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005694
    label: chromosome
  evidence_type: EXP
  original_reference_id: PMID:32789493
  qualifier: located_in
  review:
    summary: Experimental chromosome localization (SIRT6/DDB2 study); DDB2 accumulates on damaged chromatin/chromosomes after UV. Core localization.
    action: ACCEPT
    reason: Core localization; DDB2 binds chromatinized damaged DNA at chromosomes.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Chromosome {ECO:0000269|PubMed:32789493}. Note=Accumulates at sites of DNA damage following UV irradiation.
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISS
  original_reference_id: PMID:33937266
  qualifier: is_active_in
  review:
    summary: Sequence-similarity assignment that DDB2 is active in chromatin, where it binds CPDs and the CRL4(DDB2) ligase acts on damaged nucleosomes.
    action: ACCEPT
    reason: Correct core localization of activity; DDB2 binds and acts on damaged chromatin to recruit XPC.
    supported_by:
    - reference_id: PMID:33937266
      supporting_text: DDB2 must remain on damaged chromatin, however, for sufficient time to recruit and hand-off lesions to XPC
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: ISS
  original_reference_id: PMID:33937266
  qualifier: enables
  review:
    summary: Sequence-similarity transfer of damaged-DNA binding, the core molecular function of DDB2.
    action: ACCEPT
    reason: Core molecular function; redundant with IDA/IBA/TAS evidence.
    supported_by:
    - reference_id: PMID:33937266
      supporting_text: DDB2 directly binds CPDs and subsequently undergoes ubiquitination and proteasomal degradation
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: ISS
  original_reference_id: PMID:33937266
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of nucleotide-excision repair, the core biological process of DDB2 (UV-lesion recognition initiating GG-NER).
    action: ACCEPT
    reason: Core biological process; redundant with IDA/TAS evidence.
    supported_by:
    - reference_id: PMID:33937266
      supporting_text: The ubiquitin E3-ligase complex UV-DDB is required for the recognition and repair of UV-induced cyclobutane pyrimidine dimers (CPDs) lesions through NER
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: IDA
  original_reference_id: PMID:19109893
  qualifier: involved_in
  review:
    summary: Direct evidence (structural study of UV-DDB on damaged DNA) for DDB2's role in nucleotide-excision repair via lesion recognition. Core process.
    action: ACCEPT
    reason: Core biological process with direct support.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair
- term:
    id: GO:0090734
    label: site of DNA damage
  evidence_type: IDA
  original_reference_id: PMID:19109893
  qualifier: is_active_in
  review:
    summary: Direct evidence that DDB2 is active at sites of DNA damage, where the UV-DDB complex binds photolesions. Core localization of activity.
    action: ACCEPT
    reason: Correct localization of activity; DDB2 binds and acts at UV-damage sites.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Accumulates at sites of DNA damage following UV irradiation
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: IDA
  original_reference_id: PMID:22334663
  qualifier: contributes_to
  review:
    summary: Direct evidence that DDB2 (within UV-DDB) binds photolesion-containing nucleosomes/damaged DNA. Core molecular function.
    action: ACCEPT
    reason: Core molecular function with direct support.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16949367
  qualifier: enables
  review:
    summary: Interactions with DDB1, CUL4A and CUL4B from the DCAF-family study identifying DDB2 as a Cul4-Ddb1-associated substrate receptor. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real complex interactions establishing DDB2 as a DCAF, but bare protein binding is uninformative; captured by complex part_of annotations.
    supported_by:
    - reference_id: PMID:16949367
      supporting_text: we identify 18 Ddb1- and Cul4-associated factors (DCAFs)
- term:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  evidence_type: IMP
  original_reference_id: PMID:16949367
  qualifier: part_of
  review:
    summary: Mutant-phenotype evidence that DDB2 is part of a CUL4-RING E3 ligase complex (as a DCAF), its core substrate-receptor context.
    action: ACCEPT
    reason: Core complex membership; DDB2 is a CUL4-DDB1-associated factor (DCAF) substrate receptor.
    supported_by:
    - reference_id: PMID:16949367
      supporting_text: we identify 18 Ddb1- and Cul4-associated factors (DCAFs)
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IPI
  original_reference_id: PMID:11564863
  qualifier: enables
  review:
    summary: DDB2 binds the STAGA chromatin-acetylating coactivator complex (ComplexPortal CPX-900). A real but peripheral complex association.
    action: KEEP_AS_NON_CORE
    reason: Documents association with the STAGA complex (DDB connecting DNA-damage-binding to a transcriptional coactivator), peripheral to the core GG-NER/CRL4 role.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Protein, which is both involved in DNA repair and protein ubiquitination
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5696997
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization within a GG-NER/CRL4 reaction (USP24 deubiquitinates DDB2). Consistent with the core nuclear compartment.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm and multiple nuclear annotations.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5689317
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in GG-NER pre-incision complex formation.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5689861
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (XPA recruitment).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690213
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690988
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER incision reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690990
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER incision reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690991
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5690996
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5691000
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5696655
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (PARP1/2 PARylates DDB2).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5696670
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (CHD1L recruitment).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6790454
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER/XPC SUMOylation reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6790487
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (RNF111 ubiquitinates SUMOylated XPC).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0031465
    label: Cul4B-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:22334663
  qualifier: part_of
  review:
    summary: Direct evidence of DDB2 in the CUL4B-RING (CRL4B(DDB2)) ligase, which acts on photolesion-containing nucleosomes. Core complex membership.
    action: ACCEPT
    reason: Core complex membership; DDB2 is the substrate receptor of both CUL4A- and CUL4B-based CRL4(DDB2) ligases.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: which includes CUL4A or CUL4B, DDB1, DDB2 and RBX1
- term:
    id: GO:0070914
    label: UV-damage excision repair
  evidence_type: IDA
  original_reference_id: PMID:22334663
  qualifier: involved_in
  review:
    summary: Direct evidence linking DDB2/UV-DDB E3 ligase to UV-damage excision repair via monoubiquitinated-H2A-dependent nucleosome destabilization and ligase release.
    action: ACCEPT
    reason: Core biological process with direct support.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5691006
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (XPC:RAD23:CETN2 and UV-DDB bind distorted dsDNA).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5696664
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a GG-NER reaction (PARP1/2 binds DDB2).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6782943
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in the GG-NER reaction in which UV-DDB ubiquitinates XPC.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6806423
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in the reaction TP53 stimulates DDB2 expression.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952638
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 neddylation reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952639
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 neddylation reaction.
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955245
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 regulation reaction (CAND1 binds CRL4).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955285
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 regulation reaction (COMMDs displace CAND1).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956045
  qualifier: located_in
  review:
    summary: Reactome curation of DDB2 nucleoplasmic localization in a CRL4 regulation reaction (COP9 signalosome deneddylates CRL4).
    action: ACCEPT
    reason: Correct localization; redundant with IDA nucleoplasm annotation.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:12732143
  qualifier: involved_in
  review:
    summary: Direct evidence that the DDB2 complex displays ubiquitin-ligase activity (polyubiquitination), regulated by the COP9 signalosome. Reflects DDB2's substrate-receptor role in CRL4-mediated ubiquitination.
    action: ACCEPT
    reason: Supported by the demonstration of ubiquitin ligase activity in the DDB2/CUL4A/Roc1 complex.
    supported_by:
    - reference_id: PMID:12732143
      supporting_text: Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:12732143
  qualifier: contributes_to
  review:
    summary: Direct evidence that DDB2 contributes to the ubiquitin-transferase activity of the DDB2/CUL4A/Roc1 complex. DDB2 itself is the substrate receptor (not the catalytic RING), hence contributes_to is appropriate.
    action: ACCEPT
    reason: Correct use of contributes_to; DDB2 is the substrate-recognition module conferring activity on the complex, with the catalytic RING provided by RBX1/ROC1.
    supported_by:
    - reference_id: PMID:12732143
      supporting_text: Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12732143
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) in the DDB2/COP9 complex study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real DDB1 interaction but bare protein binding is uninformative; captured by complex membership.
    supported_by:
    - reference_id: PMID:12732143
      supporting_text: DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IDA
  original_reference_id: PMID:12732143
  qualifier: involved_in
  review:
    summary: Direct evidence that DDB2 complex ubiquitin ligase activity is regulated in response to UV irradiation. Reflects DDB2's UV-response role.
    action: ACCEPT
    reason: Core process; DDB2's ligase activity and lesion recognition are UV-responsive.
    supported_by:
    - reference_id: PMID:12732143
      supporting_text: CSN differentially regulates ubiquitin ligase activity of the DDB2 and CSA complexes in response to UV irradiation
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IDA
  original_reference_id: PMID:12732143
  qualifier: part_of
  review:
    summary: Generic protein-containing complex membership (the DDB2/CUL4A/Roc1/COP9 complex). A parent of the specific CRL4(DDB2) complex annotations.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; subsumed by the specific Cul4-RING E3 ligase complex annotations.
    supported_by:
    - reference_id: PMID:12732143
      supporting_text: DDB2 and CSA are each integrated into nearly identical complexes via interaction with DDB1
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:12732143
  qualifier: involved_in
  review:
    summary: Direct evidence that DDB2 is autoubiquitinated by its associated CRL4 ligase, a hallmark of its UV-induced self-degradation that limits its residence on damaged chromatin. Monoubiquitination is compatible with damaged-DNA binding, whereas polyubiquitination abolishes binding and routes DDB2 to proteasomal degradation; XPC (aided by centrin-2) competitively suppresses this ubiquitination to allow repeated rounds of repair.
    action: ACCEPT
    reason: Supported; CRL4(DDB2) ubiquitinates DDB2 itself, leading to its proteasomal degradation, an integral feature of the lesion-handoff mechanism.
    supported_by:
    - reference_id: PMID:33937266
      supporting_text: DDB2 directly binds CPDs and subsequently undergoes ubiquitination and proteasomal degradation
    - reference_id: file:human/DDB2/DDB2-deep-research-falcon.md
      supporting_text: while unmodified DDB2 binds UV-damaged DNA, **poly-ubiquitinated DDB2** is recovered predominantly unbound and **poly-ubiquitination abrogates damaged-DNA binding**, promoting proteasomal degradation after UV exposure.
- term:
    id: GO:0006289
    label: nucleotide-excision repair
  evidence_type: TAS
  original_reference_id: PMID:8407967
  qualifier: involved_in
  review:
    summary: Author statement (XP-E DNA damage binding protein characterization) of DDB2's role in nucleotide-excision repair. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with IDA/ISS evidence.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: TAS
  original_reference_id: PMID:8798680
  qualifier: enables
  review:
    summary: Author statement of DNA binding (XP-E mutations study). A parent of the specific damaged-DNA binding function.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific GO:0003684 (damaged DNA binding) better captures DDB2's selectivity for photolesions.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP)
- term:
    id: GO:0003684
    label: damaged DNA binding
  evidence_type: TAS
  original_reference_id: PMID:8407967
  qualifier: enables
  review:
    summary: Author statement of damaged-DNA binding for the XP-E DNA-damage-binding protein (DDB2). Core molecular function.
    action: ACCEPT
    reason: Core molecular function; redundant with IDA/ISS/IBA evidence.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP)
- term:
    id: GO:0006281
    label: DNA repair
  evidence_type: TAS
  original_reference_id: PMID:8798680
  qualifier: involved_in
  review:
    summary: Author statement of DDB2's involvement in DNA repair. A parent of the specific nucleotide-excision repair role.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific nucleotide-excision repair / GG-NER annotations better capture the core role.
    supported_by:
    - reference_id: file:human/DDB2/DDB2-uniprot.txt
      supporting_text: Protein, which is both involved in DNA repair and protein ubiquitination
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:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  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: GO_REF:0000114
  title: Manual transfer of experimentally-verified manual GO annotation data to homologous
    complexes by curator judgment of sequence, composition and function similarity
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11564863
  title: Human STAGA complex is a chromatin-acetylating transcription coactivator
    that interacts with pre-mRNA splicing and DNA damage-binding factors in vivo.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of the STAGA (CPX-900) protein-containing-complex-binding annotation; a peripheral DDB2 association.
- id: PMID:11705987
  title: DDB accumulates at DNA damage sites immediately after UV irradiation and
    directly stimulates nucleotide excision repair.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes nuclear accumulation of DDB at UV-damage sites and direct stimulation of NER.
- id: PMID:12732143
  title: The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially
    regulated by the COP9 signalosome in response to DNA damage.
  findings:
  - statement: DDB2 is integrated via DDB1 into a CUL4A/Roc1 ubiquitin ligase complex that displays ubiquitin ligase activity, regulated by the COP9 signalosome in response to UV.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the polyubiquitination, ubiquitin-transferase, autoubiquitination, and UV-response IDA annotations.
- id: PMID:12944386
  title: In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by
    the DDB2 gene product.
  findings:
  - statement: DDB2 (p48) localizes to both CPDs and 6-4PPs in vivo and activates recruitment of XPC to CPDs, acting as the initial recognition factor in NER.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes DDB2's role as the initial lesion sensor that hands CPDs off to XPC.
- id: PMID:14751237
  title: Human DDB2 splicing variants are dominant negative inhibitors of UV-damaged
    DNA repair.
  findings:
  - statement: Splice variants D1 and D2 act as dominant-negative inhibitors of UV-damaged DNA repair by disrupting DDB1-DDB2 complex formation and DDB1 nuclear import.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of nuclear localization (IDA) and UV-damage excision repair (IDA) annotations; characterizes the dominant-negative isoforms D1/D2.
- id: PMID:16473935
  title: The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum
    group E and targets histone H2A at UV-damaged DNA sites.
  findings:
  - statement: DDB2 is the substrate receptor of the DDB1-CUL4A ligase that monoubiquitinates histone H2A at UV-damaged sites in a photolesion-binding-dependent manner; mutations in DDB2 underlie XP-E.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes DDB2 as the DCAF substrate receptor of CRL4A targeting histone H2A; foundational for the E3-ligase role.
- id: PMID:16949367
  title: A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is
    required for S phase destruction of the replication factor Cdt1.
  findings:
  - statement: DDB2 is one of 18 identified Ddb1- and Cul4-associated factors (DCAFs) that serve as substrate receptors of CUL4 E3 ligases.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes DDB2 as a DCAF substrate receptor; source of Cul4-RING complex membership (IMP).
- id: PMID:17041588
  title: CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and
    regulates histone methylation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of DDB1/CUL4A interaction annotations; context of WD40-repeat DCAFs.
- id: PMID:17360488
  title: HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding
    protein DDB1.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HIV-1 Vpr/DDB1 study; source of a DDB1 interaction annotation, peripheral to DDB2 function.
- id: PMID:18593899
  title: The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged
    chromatin and ubiquitinates histone H2A.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the CUL4B-based UV-DDB ligase that ubiquitinates H2A on damaged chromatin; source of nuclear localization annotation.
- id: PMID:19109893
  title: Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex.
  findings:
  - statement: Crystal structure of the DDB1-DDB2 complex on damaged DNA reveals the molecular basis of photolesion recognition.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis of DDB2 damaged-DNA binding; source of NER (IDA) and site-of-DNA-damage (IDA) annotations.
- id: PMID:19966799
  title: A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors
    to the CUL4-DDB1 ubiquitin ligase machinery.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Defines the helical motif anchoring DCAF substrate receptors (including DDB2) to CUL4-DDB1; source of a DDB1 interaction annotation.
- id: PMID:21145461
  title: Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative
    proteomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: CRL network proteomics; source of a CUL4A interaction annotation.
- id: PMID:22039351
  title: 'Regulation of nucleotide excision repair by UV-DDB: prioritization of damage
    recognition to internucleosomal DNA.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; UV-DDB prioritizes internucleosomal damage recognition; source of XPC/DDB1 interaction annotations.
- id: PMID:22118460
  title: The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting,
    and activation.
  findings:
  - statement: Defines the architecture, targeting and activation of the CRL4(DDB2) ubiquitin ligase; DDB2 is the substrate receptor.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of CUL4A-RING complex membership (EXP), nuclear localization, DNA damage response, and cellular response to UV annotations.
- id: PMID:22822215
  title: Damaged DNA induced UV-damaged DNA-binding protein (UV-DDB) dimerization
    and its roles in chromatinized DNA repair.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: UV-DDB dimerization study; source of a DDB1 interaction annotation relevant to chromatinized DNA repair.
- id: PMID:22334663
  title: Monoubiquitinated histone H2A destabilizes photolesion-containing nucleosomes
    with concomitant release of UV-damaged DNA-binding protein E3 ligase.
  findings:
  - statement: Monoubiquitinated H2A destabilizes photolesion-containing nucleosomes and releases the UV-DDB E3 ligase, coupling histone ubiquitination to lesion handoff and repair.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of damaged-DNA binding (IDA), CUL4B-RING complex membership (IDA), and UV-damage excision repair (IDA) annotations.
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Quantitative interactome; source of a CUL4A interaction annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome; source of DDB1/CUL4A interaction annotations.
- id: PMID:30945288
  title: Inflammation-dependent overexpression of c-Myc enhances CRL4(DCAF4) E3 ligase
    activity and promotes ubiquitination of ST7 in colitis-associated cancer.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: CRL4(DCAF4) study; source of a CUL4A interaction annotation (CRL4 context), peripheral to DDB2.
- id: PMID:32789493
  title: The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting
    DDB2.
  findings:
  - statement: SIRT6 promotes repair of UV-induced DNA damage by targeting DDB2; DDB2 localizes to chromosome/damaged chromatin after UV.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; source of chromosome localization (EXP) annotation; links SIRT6 to DDB2 regulation in UV repair.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Neurodegeneration interactome; source of a high-throughput protein binding annotation.
- id: PMID:33937266
  title: USP44 Stabilizes DDB2 to Facilitate Nucleotide Excision Repair and Prevent
    Tumors.
  findings:
  - statement: DDB2 directly binds CPDs, undergoes ubiquitination/proteasomal degradation, and must remain on damaged chromatin to recruit and hand off lesions to XPC; USP44 deubiquitinates DDB2 to prevent premature degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; source of chromatin (ISS), damaged-DNA binding (ISS) and NER (ISS) annotations; supports DDB2 turnover/handoff model.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of DDB1/CUL4A interaction annotations.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Full text available; OpenCell endogenous-tagging interactome; source of a DDB1 interaction annotation.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Full text available; multimodal cell-map interactome; source of a CUL4A interaction annotation.
- id: PMID:8407967
  title: Characterization of a human DNA damage binding protein implicated in xeroderma
    pigmentosum E.
  findings:
  - statement: Characterizes the human DNA damage binding protein implicated in XP-E, supporting damaged-DNA binding and a NER role.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of TAS damaged-DNA binding and nucleotide-excision-repair annotations.
- id: PMID:8798680
  title: Mutations specific to the xeroderma pigmentosum group E Ddb- phenotype.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: XP-E mutation study; source of TAS DNA binding and DNA repair annotations.
- id: PMID:9418871
  title: DDB, a putative DNA repair protein, can function as a transcriptional partner
    of E2F1.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of an E2F1 interaction annotation supporting a peripheral transcriptional-partner role.
- id: file:human/DDB2/DDB2-deep-research-falcon.md
  title: Falcon deep research report for human DDB2
  findings:
  - statement: DDB2 has an N-terminal helix-loop-helix that associates with DDB1 and a seven-bladed WD40 beta-propeller that mediates DNA binding.
    supporting_text: Structural work defines an N-terminal **helix–loop–helix (HLH)** used for DDB1 association and a **7-bladed WD40 β-propeller** that mediates DNA binding, matching the WD-repeat family/domain expectations given in the prompt.
  - statement: The DDB2 propeller contacts ~7 bp around the lesion and bends the DNA by ~40 degrees with local strand separation; the DDB1-DDB2 interface is large (~3900 square angstroms).
    supporting_text: DDB2 contacts ~7 bp around the lesion and induces an approximately **40° DNA kink** with local strand separation. The DDB1–DDB2 interface is large (reported ~**3900 Å²**), consistent with stable heterodimerization.
  - statement: Polyubiquitination abrogates DDB2 damaged-DNA binding and promotes proteasomal degradation after UV, whereas unmodified DDB2 binds UV-damaged DNA.
    supporting_text: while unmodified DDB2 binds UV-damaged DNA, **poly-ubiquitinated DDB2** is recovered predominantly unbound and **poly-ubiquitination abrogates damaged-DNA binding**, promoting proteasomal degradation after UV exposure.
  - statement: XPC competitively suppresses DDB2 ubiquitination (enhanced by centrin-2), stabilizing DDB2 so it can initiate multiple rounds of repair.
    supporting_text: 'XPC competitively suppresses DDB2 ubiquitination in vitro, and this protection is enhanced by **centrin-2**, supporting a model in which XPC enables DDB2 to initiate multiple rounds of repair by limiting DDB2 degradation.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis (Scrima 2008, Matsumoto 2015, Jia 2011, Clement 2010) of DDB2 as the UV-DDB lesion sensor and CRL4(DDB2) DCAF; structural and regulatory claims cross-checked against the UniProt record and the existing experimentally curated annotations. Citations are author-year/DOI rather than PMIDs.
- id: Reactome:R-HSA-5689317
  title: Formation of the pre-incision complex in GG-NER
  findings: []
- id: Reactome:R-HSA-5689861
  title: Recruitment of XPA and release of CAK
  findings: []
- id: Reactome:R-HSA-5690213
  title: DNA polymerases delta, epsilon or kappa bind the GG-NER site
  findings: []
- id: Reactome:R-HSA-5690988
  title: 3'-incision of DNA by ERCC5 (XPG) in GG-NER
  findings: []
- id: Reactome:R-HSA-5690990
  title: 5'- incision of DNA by ERCC1:ERCC4 in GG-NER
  findings: []
- id: Reactome:R-HSA-5690991
  title: Binding of ERCC1:ERCC4 (ERCC1:XPF) to pre-incision complex in GG-NER
  findings: []
- id: Reactome:R-HSA-5690996
  title: ERCC2 and ERCC3 DNA helicases form an open bubble structure in damaged DNA
  findings: []
- id: Reactome:R-HSA-5691000
  title: TFIIH binds GG-NER site to form a verification complex
  findings: []
- id: Reactome:R-HSA-5691006
  title: XPC:RAD23:CETN2 and UV-DDB bind distorted dsDNA site
  findings: []
- id: Reactome:R-HSA-5696655
  title: PARP1 or PARP2 PARylates DDB2 and autoPARylates
  findings: []
- id: Reactome:R-HSA-5696664
  title: PARP1 or PARP2 binds DDB2 at GG-NER site
  findings: []
- id: Reactome:R-HSA-5696670
  title: CHD1L is recruited to GG-NER site
  findings: []
- id: Reactome:R-HSA-5696997
  title: USP24 deubiquitinates DDB2
  findings: []
- id: Reactome:R-HSA-6782943
  title: UV-DDB ubiquitinates XPC
  findings: []
- id: Reactome:R-HSA-6790454
  title: SUMOylation of XPC
  findings: []
- id: Reactome:R-HSA-6790487
  title: RNF111 ubiquitinates SUMOylated XPC
  findings: []
- id: Reactome:R-HSA-6806423
  title: TP53 stimulates DDB2 expression
  findings: []
- id: Reactome:R-HSA-8952638
  title: AcM-UBE2M transfers NEDD8 to CRL4 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952639
  title: NEDD8:AcM-UBE2M binds CRL4 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955245
  title: CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus
  findings: []
- id: Reactome:R-HSA-8955285
  title: COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8956045
  title: COP9 signalosome deneddylates nuclear CRL4 E3 ubiquitin ligase complex
  findings: []
core_functions:
- description: Damage-sensing subunit of the UV-DDB (DDB1-DDB2) complex that directly binds UV-induced photolesions (CPDs and 6-4PPs) in chromatinized DNA and recruits/hands off the lesion to XPC to initiate global-genome nucleotide excision repair.
  molecular_function:
    id: GO:0003684
    label: damaged DNA binding
  locations:
  - id: GO:0090734
    label: site of DNA damage
  - id: GO:0000785
    label: chromatin
  supported_by:
  - reference_id: PMID:12944386
    supporting_text: p48 activates the recruitment of XPC to CPDs and may be the initial recognition factor in the NER pathway
  - reference_id: file:human/DDB2/DDB2-uniprot.txt
    supporting_text: The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches
  directly_involved_in:
  - id: GO:0006289
    label: nucleotide-excision repair
- description: Substrate-recognition receptor (DCAF) of the CRL4(DDB2) (DDB1-CUL4A/CUL4B-RBX1) E3 ubiquitin ligase that assembles on UV-damaged chromatin and directs ubiquitination of histones (H2A, H3, H4), of XPC, and of DDB2 itself, helping remodel damaged nucleosomes and couple lesion recognition to repair.
  molecular_function:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  locations:
  - id: GO:0000785
    label: chromatin
  supported_by:
  - reference_id: PMID:16473935
    supporting_text: DDB2, as the substrate receptor of the DDB1-CUL4A-based ligase, specifically targets histone H2A for monoubiquitination in a photolesion-binding-dependent manner
  - reference_id: PMID:12732143
    supporting_text: Both complexes contain cullin 4A and Roc1 and display ubiquitin ligase activity
  in_complex:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  directly_involved_in:
  - id: GO:0000209
    label: protein polyubiquitination
proposed_new_terms: []
suggested_questions:
- question: How is DDB2's dual role balanced between productive lesion handoff to XPC and its own CRL4-mediated autoubiquitination/degradation, and what determines the timing of DDB2 turnover at a lesion?
- question: To what extent does CRL4(DDB2)-mediated histone (H2A/H3/H4) ubiquitination versus PARylation and chromatin remodeling contribute independently to nucleosome destabilization at damage sites?
- question: Why does monoubiquitination remain compatible with DDB2 damaged-DNA binding while polyubiquitination abolishes it, and how do XPC and centrin-2 set the threshold between productive lesion handoff and DDB2 degradation?
suggested_experiments:
- description: Reconstitute CRL4(DDB2) on defined nucleosomes containing a single CPD or 6-4PP and measure, by quantitative mass spectrometry, the kinetics and lysine-site specificity of histone, XPC and DDB2 ubiquitination, dissecting the contributions of CUL4A vs CUL4B.
- description: Use live-cell imaging with separation-of-function DDB2 mutants (DNA-binding-competent but ligase-dead, or autoubiquitination-resistant) to quantify lesion residence time, XPC recruitment kinetics and GG-NER efficiency for CPDs vs 6-4PPs.
- description: Using in vitro damaged-DNA binding assays with DDB2 bearing defined mono- versus poly-ubiquitin chains, and titrating XPC and centrin-2, quantify how the ubiquitination state and XPC/centrin-2 occupancy switch DDB2 between lesion-bound and degradation-bound states.

DDB2

Gene Description

Existing Annotations Review

Core Functions

Damage-sensing subunit of the UV-DDB (DDB1-DDB2) complex that directly binds UV-induced photolesions (CPDs and 6-4PPs) in chromatinized DNA and recruits/hands off the lesion to XPC to initiate global-genome nucleotide excision repair.

Substrate-recognition receptor (DCAF) of the CRL4(DDB2) (DDB1-CUL4A/CUL4B-RBX1) E3 ubiquitin ligase that assembles on UV-damaged chromatin and directs ubiquitination of histones (H2A, H3, H4), of XPC, and of DDB2 itself, helping remodel damaged nucleosomes and couple lesion recognition to repair.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human DDB2 (UniProt Q92466)

1. Target verification (gene/protein identity)

2. Key concepts and definitions (current understanding)

2.1 Global-genome nucleotide excision repair (GG-NER) damage recognition

2.2 UV-DDB and CRL4\^DDB2 ubiquitin signaling

3. Molecular function and mechanism (primary function)

3.1 DNA lesion binding and substrate/lesion specificity

3.2 Role as a damage-recognition “organizer” and XPC recruitment/handoff

4. Regulation, localization, and pathway context

4.1 Subcellular localization

4.2 Ubiquitination and protein stability (a key regulatory circuit)

4.3 Chromatin context and quantitative repair-associated observations

5. Recent developments and latest research (prioritizing 2023–2024)

5.1 DDB2 in radiotherapy and PARP inhibitor response (PDAC; 2024)

5.2 DDB2–PCNA interaction and EMT/NF-κB programs (2024)

6. Current applications and real-world implementations

6.1 Rapid biodosimetry after radiation exposure (FAST-DOSE; 2024)

6.2 Oncology biomarker hypothesis generation (preclinical)

7. Synthesis and expert-style analysis (evidence-constrained)

8. Evidence summary table

Key primary sources used (with dates and URLs)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

DDB2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul4A/Cul4B substrate receptor | WD40 | other

Projected GO annotations (1)

Note

📄 View Raw YAML