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 Ų**), 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 Ų**), 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.