id: Q9BW61
gene_symbol: DDA1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DDA1 (DET1- and DDB1-associated protein 1) is a small, evolutionarily conserved
  subunit shared by numerous CUL4-RING (CRL4) E3 ubiquitin ligase complexes. It is
  an integral, core component of DCX/CRL4 complexes built on a core of DDB1,
  cullin-4 (CUL4A or CUL4B) and RBX1, where it functions as a scaffolding subunit
  that wraps around DDB1 and the substrate receptor (DCAF) to stabilize the
  assembled ligase and promote efficient, processive substrate ubiquitination.
  DDA1 is not itself a substrate receptor and does not provide the catalytic RING;
  rather it acts as an accessory/stabilizing module that rigidifies the complex and
  positions the substrate for ubiquitin transfer. It engages DDB1 with high affinity
  (Kd in the low-nanomolar range) through a conserved extreme N-terminal segment
  (approximately the first 28 residues) that docks into a groove on the BPA
  beta-propeller of DDB1, anchoring DDA1 within the assembled ligase. It has been
  structurally and biochemically characterized as part of the DDB1-DCAF15-DDA1
  ligase that mediates aryl-sulfonamide (indisulam/E7820)-induced neosubstrate
  degradation of the splicing factor RBM39 (and its paralog RBM23), and it is also
  part of the DDD core complex (DET1-DDA1-DDB1) that recruits UBE2E-family E2
  enzymes. DDA1 is additionally an integral, structurally resolved component of the
  CRL4(CSA) ligase, where it modestly stabilizes the CSA-DDB1 module and helps
  coordinate the ubiquitination dynamics that drive transcription-coupled
  nucleotide excision repair at RNA polymerase II stalled on DNA lesions. Through
  its presence across many CRL4 complexes DDA1 broadly supports CUL4-dependent
  protein polyubiquitination and proteasomal degradation, with downstream
  consequences for diverse substrates and pathways. It localizes to the nucleus
  where most CRL4 complexes act.
existing_annotations:
- term:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic assignment of DDA1 as part of a CUL4-RING E3 ubiquitin ligase complex, its core role as a shared stabilizing subunit.
    action: ACCEPT
    reason: Core complex membership; DDA1 is an integral component of numerous DCX/CRL4 ligases; supported experimentally and conserved.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0032434
    label: regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based assignment of involvement in regulating proteasomal ubiquitin-dependent protein catabolism, consistent with DDA1 enhancing CRL4-mediated substrate degradation.
    action: ACCEPT
    reason: Correct; as a stabilizing subunit DDA1 promotes efficient CRL4-mediated ubiquitination and subsequent proteasomal degradation of substrates.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: which mediate the ubiquitination and subsequent proteasomal degradation of target proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20562859
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) from an autophagy-system interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real DDB1 interaction (core complex partner) but bare protein binding is uninformative; captured by complex membership.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: which consist of a core of DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Interactions (Q6RW13, Q96DZ9/DCAF15) from a proteome-scale interactome study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions including DCAF15 (a CRL4 substrate receptor DDA1 stabilizes), but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Component of the DCX(DCAF15) complex, also named CLR4(DCAF15) complex, composed of DCAF15, DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30564455
  qualifier: enables
  review:
    summary: Interaction with DDB1 (Q16531) from the structural study of DDA1 as a core component of CRL4-DDB1. The DDB1 contact is mediated by a conserved N-terminal segment binding the DDB1 BPA propeller with low-nanomolar affinity. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, functionally central DDB1 interaction underpinning DDA1's scaffolding role, but bare protein binding is uninformative; captured by complex membership. The specific structural mechanism (N-terminal anchor on the DDB1 BPA propeller) is recorded in the falcon findings.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: acts as a scaffolding subunit required to stabilize the complex
    - reference_id: file:human/DDA1/DDA1-deep-research-falcon.md
      supporting_text: Shabek et al. mapped DDB1 binding to a conserved **N-terminal 28-aa segment** (DDA1-NT), solved the **DDB1–DDA1-NT crystal structure at ~3.1 Å**, and localized binding to a groove on the **BPA propeller** of DDB1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Interactions (Q8IZV5, Q96DZ9-2/DCAF15 isoform, Q96KN3) from a binary interactome reference map. 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/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Interaction (O60260-5, PARK2/parkin 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/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- 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: Real DDB1 interaction but bare protein binding is uninformative; captured by complex membership.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: which consist of a core of DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1
- 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, consistent with DDA1's role in CRL4-mediated ubiquitination.
    action: ACCEPT
    reason: Correct; DDA1 contributes to CRL4-mediated protein ubiquitination as a stabilizing subunit.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IPI
  original_reference_id: PMID:31693891
  qualifier: part_of
  review:
    summary: Physical-interaction (ComplexPortal) evidence that DDA1 is part of the CUL4A-RING (CRL4A-DCAF15) ligase complex. Core complex membership.
    action: ACCEPT
    reason: Core complex membership with experimental support; DDA1 is part of CRL4(DCAF15).
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: composed of DCAF15, DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1
- term:
    id: GO:0031465
    label: Cul4B-RING E3 ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:31452512
  qualifier: part_of
  review:
    summary: Author statement (ComplexPortal) that DDA1 is part of the CUL4B-RING (CRL4B-DCAF15) ligase complex. Core complex membership.
    action: ACCEPT
    reason: Core complex membership; DDA1 is a shared subunit of CUL4A- and CUL4B-based CRL4(DCAF15) ligases.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: composed of DCAF15, DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1
- term:
    id: GO:0032814
    label: regulation of natural killer cell activation
  evidence_type: NAS
  original_reference_id: PMID:31452512
  qualifier: involved_in
  review:
    summary: Author statement linking the CRL4-DCAF15 ligase (of which DDA1 is the stabilizing subunit) to regulation of NK-cell-mediated immune surveillance; DCAF15 disruption sensitizes cancer cells to NK clearance.
    action: KEEP_AS_NON_CORE
    reason: A real but indirect, context-specific role mediated through the DCAF15 substrate receptor; peripheral to DDA1's core CRL4-stabilizing function.
    supported_by:
    - reference_id: PMID:31452512
      supporting_text: the ubiquitin ligase substrate adaptor DCAF15 strongly sensitized cancer cells to NK-mediated clearance
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IMP
  original_reference_id: PMID:31686031
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that DDA1, within the DDB1-DCAF15-DDA1 core ligase, supports polyubiquitination (E7820-mediated RBM39 degradation). Core process role.
    action: ACCEPT
    reason: Supported; the DDB1-DCAF15-DDA1 ligase polyubiquitinates RBM39, with DDA1 stabilizing the DCAF15 fold.
    supported_by:
    - reference_id: PMID:31686031
      supporting_text: We show that DCAF15 adopts a new fold stabilized by DDA1
- term:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:28302793
  qualifier: part_of
  review:
    summary: Direct evidence that DDA1 is part of a CUL4-RING (CRL4-DCAF15) E3 ligase complex mediating RBM39 degradation. Core complex membership.
    action: ACCEPT
    reason: Core complex membership with direct support.
    supported_by:
    - reference_id: PMID:28302793
      supporting_text: indisulam promotes the recruitment of RBM39 (RNA binding motif protein 39) to the CUL4-DCAF15 E3 ubiquitin ligase
- term:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:31686031
  qualifier: part_of
  review:
    summary: Direct (cryo-EM) evidence that DDA1 is part of the DDB1-DCAF15-DDA1 core CRL4 ligase complex. Core complex membership.
    action: ACCEPT
    reason: Core complex membership with direct structural support.
    supported_by:
    - reference_id: PMID:31686031
      supporting_text: the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39
- 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; establishes DDA1 association with the CUL4-DDB1 core. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real core-complex interactions but bare protein binding is uninformative; captured by complex membership.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: which consist of a core of DDB1, cullin-4 (CUL4A or CUL4B), DDA1 and RBX1
- term:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:16949367
  qualifier: part_of
  review:
    summary: Direct evidence (DCAF-family study) that DDA1 is part of a CUL4-RING E3 ligase complex. Core complex membership.
    action: ACCEPT
    reason: Core complex membership with direct support.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952638
  qualifier: located_in
  review:
    summary: Reactome curation of DDA1 nucleoplasmic localization within a CRL4 neddylation reaction. Consistent with the nuclear site of CRL4 action.
    action: ACCEPT
    reason: Correct localization; CRL4 complexes containing DDA1 act in the nucleus.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952639
  qualifier: located_in
  review:
    summary: Reactome curation of DDA1 nucleoplasmic localization within a CRL4 neddylation reaction.
    action: ACCEPT
    reason: Correct localization; redundant with the other nucleoplasm annotations.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955245
  qualifier: located_in
  review:
    summary: Reactome curation of DDA1 nucleoplasmic localization within a CRL4 regulation reaction (CAND1 binds CRL4).
    action: ACCEPT
    reason: Correct localization; redundant with the other nucleoplasm annotations.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955285
  qualifier: located_in
  review:
    summary: Reactome curation of DDA1 nucleoplasmic localization within a CRL4 regulation reaction (COMMDs displace CAND1).
    action: ACCEPT
    reason: Correct localization; redundant with the other nucleoplasm annotations.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956045
  qualifier: located_in
  review:
    summary: Reactome curation of DDA1 nucleoplasmic localization within a CRL4 regulation reaction (COP9 signalosome deneddylates CRL4).
    action: ACCEPT
    reason: Correct localization; redundant with the other nucleoplasm annotations.
    supported_by:
    - reference_id: file:human/DDA1/DDA1-uniprot.txt
      supporting_text: Functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes
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: 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: Defines the family of DDB1- and CUL4-associated factors (DCAFs); DDA1 associates with the CUL4-DDB1 core.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes the DCAF/CUL4-DDB1 framework within which DDA1 acts; source of complex-membership and DDB1/CUL4 interaction annotations.
- id: PMID:20562859
  title: Network organization of the human autophagy system.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Autophagy-system interactome; source of a DDB1 interaction annotation.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale interactome; source of high-throughput protein binding annotations (incl. DCAF15).
- id: PMID:28302793
  title: Anticancer sulfonamides target splicing by inducing RBM39 degradation via
    recruitment to DCAF15.
  findings:
  - statement: Indisulam recruits RBM39 to the CUL4-DCAF15 E3 ligase (containing DDA1) for polyubiquitination and proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the CRL4-DCAF15 (with DDA1) sulfonamide-induced RBM39 degradation; source of complex-membership annotation.
- id: PMID:30564455
  title: Structural insights into DDA1 function as a core component of the CRL4-DDB1
    ubiquitin ligase.
  findings:
  - statement: Structural characterization of DDA1 as a core scaffolding/stabilizing component of the CRL4-DDB1 ubiquitin ligase.
    reference_section_type: TITLE
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; the principal structural study defining DDA1's core scaffolding role in CRL4-DDB1; source of a DDB1 interaction annotation.
- id: PMID:31452512
  title: Systematic identification of cancer cell vulnerabilities to natural killer
    cell-mediated immune surveillance.
  findings:
  - statement: DCAF15 (the substrate receptor of a CRL4 complex containing DDA1) disruption sensitizes cancer cells to NK-mediated clearance; cohesin members are endogenous DCAF15 substrates.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; source of CUL4B-RING complex membership (NAS) and the peripheral NK-cell-regulation (NAS) annotations, both mediated via DCAF15.
- id: PMID:31686031
  title: Structural complementarity facilitates E7820-mediated degradation of RBM39
    by DCAF15.
  findings:
  - statement: Cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase bound to RBM39; DCAF15 adopts a new fold stabilized by DDA1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; directly demonstrates DDA1 stabilizing the DCAF15 fold within the CRL4 core; source of polyubiquitination (IMP) and complex-membership (IDA) annotations.
- id: PMID:31693891
  title: Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15.
  findings:
  - statement: Aryl sulfonamides recruit RBM39 and its paralog RBM23 to the CRL4-DCAF15 ligase (containing DDA1) for ubiquitination and degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; source of CUL4A-RING complex membership (IPI/ComplexPortal) annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of high-throughput protein binding annotations (incl. DCAF15 isoform).
- 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: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: file:human/DDA1/DDA1-deep-research-falcon.md
  title: Falcon deep research report for human DDA1
  findings:
  - statement: DDA1 binds DDB1 with high affinity through a conserved extreme N-terminal segment (~first 28 residues) that docks into a groove on the BPA beta-propeller of DDB1, defining its anchoring mechanism within CRL4 ligases.
    supporting_text: Shabek et al. mapped DDB1 binding to a conserved **N-terminal 28-aa segment** (DDA1-NT), solved the **DDB1–DDA1-NT crystal structure at ~3.1 Å**, and localized binding to a groove on the **BPA propeller** of DDB1
  - statement: DDA1 is best supported as a small structural/regulatory subunit of DDB1-CUL4 ligases rather than an enzyme, modulating ligase architecture and ubiquitination output in a context-dependent manner.
    supporting_text: 'DDA1 is not an enzyme** (no independent catalytic reaction is described). Instead, it is best supported as a **small structural/regulatory subunit** of certain DDB1–CUL4 E3 ligase assemblies that can modulate ligase architecture and ubiquitination output in a **context-dependent** manner'
  - statement: DDA1 is an integral component of CRL4(CSA) that coordinates ubiquitination dynamics during transcription-coupled nucleotide excision repair (TC-NER) and is required for efficient repair turnover/progression.
    supporting_text: DDA1 was identified as a **CSA interactor** by single-step complex isolation/MS and shown by cryo-EM to be an **integral CRL4CSA component**; functionally, DDA1 was concluded to **coordinate ubiquitination dynamics during TC-NER** and be **required for efficient turnover/progression** of the repair process
  - statement: DDA1 provides a modest but reproducible thermal stabilization of the CSA-DDB1 module, with stabilization driven mainly by DDA1-DDB1 contacts.
    supporting_text: DDA1 provided a modest, reproducible **~1 °C** thermal stabilization of CSA–DDB1 measured by nanoDSF, and truncation removing a CSA-interacting helix had a similar stabilization, implying stabilization is driven mainly by **DDA1–DDB1** contacts
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis (Shabek 2018 Cell Discovery, Pick 2007 MCB, Schiffmacher 2024 Nat Commun, Pines 2023) of DDA1 as a small DDB1-anchored CRL4 stabilizing subunit and a TC-NER CRL4(CSA) component; the N-terminal DDB1-binding mechanism and the new CRL4(CSA)/TC-NER role are consistent with the UniProt record and existing structural annotations. Citations are author-year/DOI rather than PMIDs.
- 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: Shared core scaffolding/stabilizing subunit of CUL4-RING (CRL4/DCX) E3 ubiquitin ligase complexes (DDB1-CUL4A/CUL4B-RBX1 with a DCAF receptor), where DDA1 rigidifies the assembly and the substrate receptor fold to promote efficient CRL4-mediated polyubiquitination and proteasomal degradation of substrates. DDA1 is neither the substrate receptor nor the catalytic RING.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  contributes_to_molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005654
    label: nucleoplasm
  supported_by:
  - reference_id: file:human/DDA1/DDA1-uniprot.txt
    supporting_text: acts as a scaffolding subunit required to stabilize the complex
  - reference_id: PMID:31686031
    supporting_text: We show that DCAF15 adopts a new fold stabilized by DDA1
  - reference_id: file:human/DDA1/DDA1-deep-research-falcon.md
    supporting_text: Shabek et al. mapped DDB1 binding to a conserved **N-terminal 28-aa segment** (DDA1-NT), solved the **DDB1–DDA1-NT crystal structure at ~3.1 Å**, and localized binding to a groove on the **BPA propeller** of DDB1
  in_complex:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  directly_involved_in:
  - id: GO:0000209
    label: protein polyubiquitination
- description: As an integral component of the CRL4(CSA) ligase, DDA1 coordinates the ubiquitination dynamics that drive transcription-coupled nucleotide excision repair at RNA polymerase II stalled on DNA lesions, modestly stabilizing the CSA-DDB1 module and supporting efficient repair turnover/progression.
  molecular_function:
    id: GO:0005198
    label: structural molecule activity
  contributes_to_molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005654
    label: nucleoplasm
  supported_by:
  - reference_id: file:human/DDA1/DDA1-deep-research-falcon.md
    supporting_text: DDA1 was identified as a **CSA interactor** by single-step complex isolation/MS and shown by cryo-EM to be an **integral CRL4CSA component**; functionally, DDA1 was concluded to **coordinate ubiquitination dynamics during TC-NER** and be **required for efficient turnover/progression** of the repair process
  in_complex:
    id: GO:0080008
    label: Cul4-RING E3 ubiquitin ligase complex
  directly_involved_in:
  - id: GO:0006283
    label: transcription-coupled nucleotide-excision repair
proposed_new_terms: []
suggested_questions:
- question: Across the full repertoire of CRL4 complexes, which substrate receptors (DCAFs) depend most strongly on DDA1 for assembly/activity, and is DDA1 dispensable for some?
- question: Does DDA1 contribute only to complex stability and substrate positioning, or does it also influence ubiquitin-chain processivity, linkage type, or neddylation/deneddylation dynamics of CRL4 ligases?
- question: In CRL4(CSA)-dependent transcription-coupled repair, does DDA1 act primarily by stabilizing the CSA-DDB1 module, by tuning the residence time/ubiquitination progression on lesion-stalled RNA polymerase II, or both, and which TC-NER substrates (e.g., CSB, UVSSA, RNAPII) depend on DDA1 for timely turnover?
suggested_experiments:
- description: Compare RBM39 (and endogenous substrate) ubiquitination kinetics in reconstituted DDB1-CUL4-RBX1-DCAF complexes with and without DDA1, measuring effects on substrate affinity, ubiquitin-transfer rate, and processivity.
- description: Perform quantitative proteomics of DDA1-knockout versus wild-type cells to define which CRL4 substrate pools are stabilized, distinguishing DDA1-dependent from DDA1-independent CRL4 functions.
- description: In DDA1-depleted cells, measure TC-NER kinetics (e.g., recovery of RNA synthesis after UV, RNAPII clearance from lesions, and ubiquitination of CSB/UVSSA) to test whether DDA1 is required for efficient CRL4(CSA)-driven repair progression, and reconstitute CRL4(CSA) in vitro +/- DDA1 to dissect its effect on ubiquitination dynamics.