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.
| 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 Ų**), 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 |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
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.
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