id: Q9NZJ0
gene_symbol: DTL
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  DTL (also known as CDT2, DCAF2, L2DTL, RAMP) is the substrate-recognition
  subunit (DCAF/substrate receptor) of the CRL4(CDT2) E3 ubiquitin ligase, a
  DDB1-CUL4 (CUL4A or CUL4B)-RBX1 cullin-RING ligase. DTL is a nuclear WD40-repeat
  beta-propeller protein that docks onto the DDB1 adaptor of the CUL4 scaffold via
  its WDXR/DDB1-binding motifs and confers substrate specificity to the complex.
  CRL4(CDT2) couples substrate ubiquitination to DNA-bound (chromatin-loaded) PCNA:
  substrates are recruited through a specialized PIP-degron (a PIP box bearing a
  basic "K+4" residue) that simultaneously engages PCNA on chromatin and the DTL
  propeller, so that ubiquitination occurs specifically at sites of DNA replication
  and repair. Through this PCNA-coupled mechanism CRL4(CDT2) drives the
  polyubiquitination and proteasomal degradation of the replication-licensing factor
  CDT1, the CDK inhibitor CDKN1A/p21, the histone H4K20 methyltransferase SET8/KMT5A,
  the helicase FBH1, and SDE2, and also targets CRY1 to influence the circadian
  clock. This activity prevents DNA re-replication, enforces the radiation-induced
  early G2/M checkpoint, and maintains genome stability. In undamaged proliferating
  cells CRL4(CDT2) additionally monoubiquitinates PCNA at Lys164 to promote
  translesion DNA synthesis. DTL itself is cell-cycle regulated: it peaks in G1/S,
  is degraded in mitosis by APC/C-Cdh1, and is controlled by SCF(FBXO11). DTL
  localizes to the nucleus/nucleoplasm and nuclear matrix, associates with chromatin,
  and is found at the centrosome during mitosis. DTL is frequently overexpressed in
  cancers such as hepatocellular carcinoma.
alternative_products:
- name: '1'
  id: Q9NZJ0-1
- name: '2'
  id: Q9NZJ0-2
  sequence_note: VSP_022879, VSP_022880, VSP_022881
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of nuclear localization, where DTL acts as the substrate receptor of the nuclear CRL4(CDT2) ligase.
    action: ACCEPT
    reason: Correct core localization; DTL is a nuclear protein and the CRL4(CDT2) ligase acts in the nucleus on chromatin-bound substrates. Supported experimentally and by UniProt subcellular location.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in proteasome-mediated degradation, the core biological role of DTL as the receptor of CRL4(CDT2) targeting CDT1, p21, SET8 and others for proteasomal destruction.
    action: ACCEPT
    reason: Core biological process; directly supported by experimental degradation studies (CDT1, p21, CRY1, SDE2) and conserved across the Cdt2 family.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2
- term:
    id: GO:0007095
    label: mitotic G2 DNA damage checkpoint signaling
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of a role in the G2/M DNA damage checkpoint, consistent with the experimentally demonstrated requirement for DTL/CDT2 in the early radiation-induced G2/M checkpoint.
    action: ACCEPT
    reason: Supported by IMP evidence (PMID:17085480, zebrafish and human DTL) and conserved across the family.
    supported_by:
    - reference_id: PMID:17085480
      supporting_text: dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assignment of adaptor activity, capturing DTL's core molecular function as the substrate-recognition subunit that bridges substrates (and PCNA) to the CUL4-DDB1 ligase core.
    action: ACCEPT
    reason: Core molecular function. DTL is a DCAF/substrate receptor that links substrates to the CRL4 ligase; "protein-macromolecule adaptor activity" is the most informative MF term available for a substrate receptor and is preferred over bare protein binding. Substrate recruitment occurs through a PIP-degron that simultaneously engages chromatin-bound PCNA and the DTL propeller, restricting ubiquitination to sites of DNA synthesis/repair.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis
    - reference_id: file:human/DTL/DTL-deep-research-falcon.md
      supporting_text: 'Canonical CRL4^CDT2 substrates contain a **PIP-degron**: a PCNA-interacting PIP motif plus an adjacent basic signature (often described as Arg/Lys residues downstream of the PIP box) that transforms PCNA binding into a degradation signal for CRL4^CDT2.'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated electronic assignment of nuclear localization, redundant with experimental and IBA evidence.
    action: ACCEPT
    reason: Correct core localization, redundant with IDA and IBA nucleus annotations.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- 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, consistent with the PCNA/chromatin-coupled mechanism of CRL4(CDT2).
    action: ACCEPT
    reason: Correct; DTL acts on chromatin-bound PCNA at replication/repair sites and UniProt lists Chromosome as a subcellular location.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Chromosome.
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of centrosome localization from the UniProt subcellular location; DTL is recruited to centrosomes during mitosis.
    action: KEEP_AS_NON_CORE
    reason: Documented localization (also IDA in PMID:17106265) but peripheral to the core nuclear PCNA-coupled ubiquitination function; cytoplasmic/centrosomal pool reflects mitotic relocalization.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome.
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of involvement in the DNA damage response, consistent with CRL4(CDT2)-mediated degradation of CDT1 and p21 after DNA damage/UV.
    action: ACCEPT
    reason: Correct; redundant with IDA/IMP DNA damage response annotations.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication
- term:
    id: GO:0031965
    label: nuclear membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of nuclear membrane (nucleoplasmic-side peripheral membrane) localization from the UniProt subcellular location.
    action: KEEP_AS_NON_CORE
    reason: Reflects the UniProt "Nucleus membrane; Peripheral membrane protein; Nucleoplasmic side" annotation, but the functionally dominant compartment is the nucleoplasm/chromatin; nuclear-membrane association is a sub-localization detail.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Nucleus membrane; Peripheral membrane protein; Nucleoplasmic side.
- term:
    id: GO:0045732
    label: positive regulation of protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of positive regulation of protein catabolism, consistent with DTL promoting degradation of CRL4(CDT2) substrates.
    action: ACCEPT
    reason: Correct; redundant with the IMP annotation of the same term and with the proteasome-mediated catabolism annotations.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17041588
  qualifier: enables
  review:
    summary: IntAct interaction with DDB1 (Q16531), the adaptor through which DTL joins the CUL4 ligase. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally important DTL-DDB1 interaction, but bare protein binding is uninformative per curation guidelines; the relationship is captured by the complex part_of and adaptor-activity annotations.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'Q9NZJ0; Q16531: DDB1; NbExp=6; IntAct=EBI-1176075, EBI-350322'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: High-throughput interactome interaction (with VHL isoform P40337-2). 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/DTL/DTL-uniprot.txt
      supporting_text: 'Q9NZJ0; P40337-2: VHL; NbExp=3; IntAct=EBI-1176075, EBI-12157263'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific interactome interaction with DDB1 (Q16531). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome capturing the DTL-DDB1 association; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'Q9NZJ0; Q16531: DDB1; NbExp=6; IntAct=EBI-1176075, EBI-350322'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging interactome interaction with DDB1 (Q16531). 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/DTL/DTL-uniprot.txt
      supporting_text: 'Q9NZJ0; Q16531: DDB1; NbExp=6; IntAct=EBI-1176075, EBI-350322'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36931259
  qualifier: enables
  review:
    summary: Interaction with 14-3-3 protein YWHAE (P62258) from a 14-3-3 chaperone-network study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real DTL-YWHAE interaction (consistent with DTL phosphorylation), but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'Q9NZJ0; P62258: YWHAE; NbExp=4; IntAct=EBI-1176075, EBI-356498'
- 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(CDT2)-mediated ubiquitination DTL confers.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific polyubiquitination, monoubiquitination and proteasomal-catabolism annotations better capture the role.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0030174
    label: regulation of DNA-templated DNA replication initiation
  evidence_type: NAS
  original_reference_id: PMID:16861906
  qualifier: involved_in
  review:
    summary: CRL4(CDT2)-dependent degradation of the licensing factor CDT1 controls replication initiation/licensing, preventing re-replication.
    action: ACCEPT
    reason: Core biological role; DTL controls CDT1 levels to regulate replication licensing, supported experimentally across multiple studies.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:16861906
  qualifier: part_of
  review:
    summary: DTL is a component of the CUL4A-RING (CRL4) ligase complex.
    action: ACCEPT
    reason: Core complex membership; DTL/CDT2 is the substrate receptor of CRL4(CDT2), supported by IDA in multiple studies and the UniProt SUBUNIT description.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Component of the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)), at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1
- term:
    id: GO:0031465
    label: Cul4B-RING E3 ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:16861906
  qualifier: part_of
  review:
    summary: DTL is also a component of the CUL4B variant of the CRL4(CDT2) ligase complex.
    action: ACCEPT
    reason: Core complex membership; the complex uses either CUL4A or CUL4B (ComplexPortal CPX-2777 CUL4B variant), supported by IDA (PMID:18794347).
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1
- term:
    id: GO:1901987
    label: regulation of cell cycle phase transition
  evidence_type: NAS
  original_reference_id: PMID:16861906
  qualifier: involved_in
  review:
    summary: CRL4(CDT2) regulates cell-cycle phase transitions through degradation of CDT1 and p21.
    action: KEEP_AS_NON_CORE
    reason: Correct but a general developmental/cell-cycle consequence of the core substrate-degradation function; more specific cell-cycle annotations (G2/M transition, G2 checkpoint) capture the role.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: required for cell cycle control, DNA damage response and translesion DNA synthesis
- 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 DTL's nuclear site of action.
    action: ACCEPT
    reason: IDA-supported nucleoplasm localization agrees with the core nuclear/chromatin function.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23213251
  qualifier: enables
  review:
    summary: Interaction with CDKN1A/p21 (P38936), a key CRL4(CDT2) substrate, captured in the TRIM39/p21 study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally meaningful DTL-p21 substrate interaction, but bare protein binding is uninformative; substrate relationship captured by catabolic-process annotations.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Interacts with CDKN1A (PubMed:23213251)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26431207
  qualifier: enables
  review:
    summary: Interaction with CRY1 (Q16526), a CRL4(CDT2) substrate in circadian regulation. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real DTL-CRY1 substrate interaction, but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Interacts with CRY1 (PubMed:26431207)
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:26431207
  qualifier: located_in
  review:
    summary: Direct experimental evidence for nuclear localization of DTL in the CRY1/circadian study.
    action: ACCEPT
    reason: IDA-supported core nuclear localization.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:26431207
  qualifier: involved_in
  review:
    summary: Mutant/depletion-phenotype evidence that CRL4(CDT2) drives ubiquitin-dependent degradation of CRY1 (depletion of Cdt2 stabilizes CRY1).
    action: ACCEPT
    reason: Core biological process with experimental support; consistent with DTL's substrate-degradation role.
    supported_by:
    - reference_id: PMID:26431207
      supporting_text: Depletion of the major components of this E3 ligase complex, including Ddb1, Cdt2, and Cdt2-cofactor Pcna, leads to CRY1 stabilization in cultured cells or in the mouse liver
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27906959
  qualifier: enables
  review:
    summary: Interaction with SDE2 (Q6IQ49), a CRL4(CDT2) substrate cleaved and degraded in the replication-stress response. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real DTL-SDE2 substrate interaction, but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:27906959
      supporting_text: The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner
- term:
    id: GO:0007095
    label: mitotic G2 DNA damage checkpoint signaling
  evidence_type: IMP
  original_reference_id: PMID:17085480
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence (zebrafish and human DTL) that DTL/CDT2 is essential for the early radiation-induced G2/M checkpoint, by a CDT1-independent mechanism.
    action: ACCEPT
    reason: Core biological process with direct experimental support.
    supported_by:
    - reference_id: PMID:17085480
      supporting_text: dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IMP
  original_reference_id: PMID:16949367
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that Cdt2 is required to destroy Cdt1 in S phase and after DNA damage, preventing re-replication and checkpoint activation.
    action: ACCEPT
    reason: Core biological process; depletion of Cdt2 causes rereplication and checkpoint activation.
    supported_by:
    - reference_id: PMID:16949367
      supporting_text: Depletion of human Cdt2 causes rereplication and checkpoint activation.
- term:
    id: GO:0010971
    label: positive regulation of G2/M transition of mitotic cell cycle
  evidence_type: IMP
  original_reference_id: PMID:16949367
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking DTL to G2/M progression via prevention of re-replication and CDT1 control.
    action: MARK_AS_OVER_ANNOTATED
    reason: Supported by Cdt2 depletion phenotypes, but the directionality ("positive regulation of G2/M transition") is an indirect consequence of preventing re-replication/checkpoint activation rather than a direct promotive function. DTL/CDT2 restrains rereplication by degrading CDT1/p21; the G2/M-progression phenotype is downstream of checkpoint relief, so the directional term over-reaches relative to DTL's actual mechanism.
    supported_by:
    - reference_id: PMID:16949367
      supporting_text: Depletion of human Cdt2 causes rereplication and checkpoint activation.
- term:
    id: GO:0045732
    label: positive regulation of protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:16949367
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that DTL/Cdt2 promotes the destruction of the replication factor Cdt1.
    action: ACCEPT
    reason: Core biological role; DTL is required for S-phase and DNA-damage-induced degradation of CDT1.
    supported_by:
    - reference_id: PMID:16949367
      supporting_text: functions in Xenopus egg extracts and human cells to destroy the replication licensing protein Cdt1 in S phase and after DNA damage
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16949367
  qualifier: enables
  review:
    summary: Interactions with DDB1 (Q16531) and CUL4A (Q13619) establishing DTL's membership in the CUL4-DDB1 ligase. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the core DTL-DDB1/CUL4 interactions, but bare protein binding is uninformative; captured by the complex part_of and adaptor annotations.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: Interacts with DDB1 (PubMed:16949367, PubMed:23478445)
- 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 (DDB1-binding-dead mutant) that DTL is part of the CUL4-DDB1 (CRL4) E3 ligase complex.
    action: ACCEPT
    reason: Core complex membership; the R246A mutant blocks DDB1 association and CRL4(DTL) ubiquitination, confirming DTL is a bona fide complex subunit.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'R->A: Blocks association with DDB1 and ubiquitination by DCX(DTL).'
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:21628527
  qualifier: part_of
  review:
    summary: Direct evidence placing DTL/CDT2 in the CRL4A(CDT2) ligase that ubiquitinates p21, Cdt1 and Set8 using specific E2s (UBCH8, UBE2G).
    action: ACCEPT
    reason: Core complex membership with direct experimental support.
    supported_by:
    - reference_id: PMID:21628527
      supporting_text: CRL4(Cdt2) utilizes two different UBCs to target different substrates
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5652005
  qualifier: located_in
  review:
    summary: Reactome curation of DTL nucleoplasm localization within the PCNA monoubiquitination (TLS) reaction. Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA nucleoplasm evidence.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5652009
  qualifier: located_in
  review:
    summary: Reactome curation of DTL nucleoplasm localization (PCNA monoubiquitination reaction). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA nucleoplasm evidence.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952638
  qualifier: located_in
  review:
    summary: Reactome curation of DTL nucleoplasm localization (CRL4 neddylation reaction). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA nucleoplasm evidence.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952639
  qualifier: located_in
  review:
    summary: Reactome curation of DTL nucleoplasm localization (NEDD8 binding to CRL4). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA nucleoplasm evidence.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955245
  qualifier: located_in
  review:
    summary: Reactome curation of DTL nucleoplasm localization (CAND1 binding to nuclear CRL4). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA nucleoplasm evidence.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955285
  qualifier: located_in
  review:
    summary: Reactome curation of DTL nucleoplasm localization (COMMD displacement of CAND1). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA nucleoplasm evidence.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956045
  qualifier: located_in
  review:
    summary: Reactome curation of DTL nucleoplasm localization (COP9 signalosome deneddylates nuclear CRL4). Core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with IDA nucleoplasm evidence.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:26431207}'
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: TAS
  original_reference_id: PMID:17085480
  qualifier: involved_in
  review:
    summary: Author statement that DTL drives polyubiquitination of CRL4(CDT2) substrates (CDT1). Core ubiquitination process.
    action: ACCEPT
    reason: Core process; CRL4(DTL) assembles polyubiquitin chains on CDT1 to target it for degradation.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:18794347
  qualifier: involved_in
  review:
    summary: Direct evidence that CRL4(CDT2) polyubiquitinates p21 in a PCNA-dependent manner. Core ubiquitination process.
    action: ACCEPT
    reason: Core process with direct experimental support (in vivo and in vitro p21 ubiquitylation).
    supported_by:
    - reference_id: PMID:18794347
      supporting_text: The CRL4(Cdt2) E3 ubiquitin ligase ubiquitylates p21 both in vivo and in vitro
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:18794347
  qualifier: contributes_to
  review:
    summary: DTL contributes to the ubiquitin-protein transferase activity of the CRL4(CDT2) holoenzyme (the catalytic RING is RBX1). The "contributes_to" qualifier correctly reflects that the activity is a property of the complex.
    action: ACCEPT
    reason: Correct use of contributes_to; DTL is required for, but is not itself, the catalytic RING. Activity is demonstrated by in vitro/in vivo p21 ubiquitylation requiring Cdt2.
    supported_by:
    - reference_id: PMID:18794347
      supporting_text: The CRL4(Cdt2) E3 ubiquitin ligase ubiquitylates p21 both in vivo and in vitro
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:20129063
  qualifier: contributes_to
  review:
    summary: DTL contributes to CRL4(CDT2) ubiquitin-transferase activity that monoubiquitinates PCNA at Lys164 in vitro.
    action: ACCEPT
    reason: Correct use of contributes_to; the complex monoubiquitinates PCNA at Lys164 in vitro, an activity dependent on the CRL4(CDT2) holoenzyme.
    supported_by:
    - reference_id: PMID:20129063
      supporting_text: In vitro, CRL4(Cdt2) monoubiquitinates PCNA at Lys164, the same residue that is monoubiquitinated by Rad18.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18794347
  qualifier: enables
  review:
    summary: Interaction with CDKN1A/p21 (P38936), the substrate ubiquitinated by CRL4(CDT2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real DTL-p21 substrate interaction, but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:18794347
      supporting_text: Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17106265
  qualifier: located_in
  review:
    summary: Direct experimental evidence (immunostaining/fractionation) that L2DTL/DTL localizes to the nucleus in interphase.
    action: ACCEPT
    reason: IDA-supported core nuclear localization.
    supported_by:
    - reference_id: PMID:17106265
      supporting_text: L2DTL protein located to the nucleus in interphase and centered to centrosomes
- term:
    id: GO:0005813
    label: centrosome
  evidence_type: IDA
  original_reference_id: PMID:17106265
  qualifier: located_in
  review:
    summary: Direct experimental evidence that DTL centers to centrosomes (colocalizing with gamma-tubulin and Aurora-A) through the cell cycle.
    action: KEEP_AS_NON_CORE
    reason: Real, directly demonstrated centrosomal localization, but peripheral to the core nuclear PCNA-coupled ubiquitination function.
    supported_by:
    - reference_id: PMID:17106265
      supporting_text: centered to centrosomes, with colocalization of gamma-tubulin and Aurora-A, throughout the cell cycle, and cofractionated with gamma-tubulin
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:17085480
  qualifier: involved_in
  review:
    summary: Author statement that DTL is required for CUL4-DDB1-mediated ubiquitin-dependent degradation of CDT1. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with IMP/IDA degradation annotations.
    supported_by:
    - reference_id: PMID:17085480
      supporting_text: DTL associates with the CUL4-DDB1 E3 ubiquitin ligase and is required for CDT1 down-regulation
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:18794347
  qualifier: involved_in
  review:
    summary: Direct evidence that CRL4(CDT2) mediates ubiquitin-dependent degradation of p21 after UV. Core process.
    action: ACCEPT
    reason: Core biological process with direct experimental support.
    supported_by:
    - reference_id: PMID:18794347
      supporting_text: PCNA promotes the ubiquitylation and degradation of the CDK inhibitor p21 in cells irradiated with low dose of ultraviolet (UV)
- term:
    id: GO:0006513
    label: protein monoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:20129063
  qualifier: involved_in
  review:
    summary: Direct evidence that CRL4(CDT2) monoubiquitinates PCNA at Lys164 in proliferating cells, independent of Rad18. Core process distinct from the degradative polyubiquitination.
    action: ACCEPT
    reason: Core process with direct experimental support; establishes a non-degradative monoubiquitination activity of CRL4(CDT2).
    supported_by:
    - reference_id: PMID:20129063
      supporting_text: the CRL4(Cdt2) E3 ubiquitin ligase complex promotes PCNA monoubiqutination in proliferating cells in the absence of external DNA damage independent of Rad18
- term:
    id: GO:0006974
    label: DNA damage response
  evidence_type: IDA
  original_reference_id: PMID:20129063
  qualifier: involved_in
  review:
    summary: Direct evidence linking CRL4(CDT2)-mediated PCNA monoubiquitination to translesion DNA synthesis, a DNA damage tolerance response.
    action: ACCEPT
    reason: Core process; CRL4(CDT2) function is tightly tied to DNA replication-associated stress and damage tolerance.
    supported_by:
    - reference_id: PMID:20129063
      supporting_text: CRL4(Cdt2) regulates PCNA-dependent TLS associated with stresses accompanying DNA replication.
- term:
    id: GO:0009411
    label: response to UV
  evidence_type: IDA
  original_reference_id: PMID:18794347
  qualifier: involved_in
  review:
    summary: Direct evidence that CRL4(CDT2) mediates UV-induced p21 ubiquitylation and degradation. Core process in the UV/DNA-damage response.
    action: ACCEPT
    reason: Core process with direct experimental support; p21 degradation occurs specifically after UV irradiation.
    supported_by:
    - reference_id: PMID:18794347
      supporting_text: PCNA promotes the ubiquitylation and degradation of the CDK inhibitor p21 in cells irradiated with low dose of ultraviolet (UV)
- term:
    id: GO:0019985
    label: translesion synthesis
  evidence_type: IDA
  original_reference_id: PMID:20129063
  qualifier: involved_in
  review:
    summary: Direct evidence that CRL4(CDT2)-dependent PCNA monoubiquitination is required for translesion DNA synthesis in nondamaged cells. Core process.
    action: ACCEPT
    reason: Core process with direct experimental support.
    supported_by:
    - reference_id: PMID:20129063
      supporting_text: CRL4(Cdt2) is required for TLS in nondamaged cells via a mechanism that is dependent on PCNA monoubiquitination
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:17085480
  qualifier: part_of
  review:
    summary: Direct evidence that DTL associates with the CUL4-DDB1 (CRL4A) E3 ligase complex.
    action: ACCEPT
    reason: Core complex membership with direct experimental support.
    supported_by:
    - reference_id: PMID:17085480
      supporting_text: DTL associates with the CUL4-DDB1 E3 ubiquitin ligase
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:18794347
  qualifier: part_of
  review:
    summary: Direct evidence that DTL/Cdt2 is part of the CRL4A(CDT2) complex that ubiquitinates p21.
    action: ACCEPT
    reason: Core complex membership; redundant with other IDA complex annotations.
    supported_by:
    - reference_id: PMID:18794347
      supporting_text: Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex.
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:20129063
  qualifier: part_of
  review:
    summary: Direct evidence that DTL/Cdt2 is part of the CRL4A(CDT2) complex that monoubiquitinates PCNA.
    action: ACCEPT
    reason: Core complex membership; redundant with other IDA complex annotations.
    supported_by:
    - reference_id: PMID:20129063
      supporting_text: the CRL4(Cdt2) E3 ubiquitin ligase complex promotes PCNA monoubiqutination
- term:
    id: GO:0031465
    label: Cul4B-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:18794347
  qualifier: part_of
  review:
    summary: Direct evidence that DTL/Cdt2 is part of the CUL4B-variant CRL4(CDT2) complex.
    action: ACCEPT
    reason: Core complex membership; the CRL4(CDT2) complex uses either CUL4A or CUL4B.
    supported_by:
    - reference_id: file:human/DTL/DTL-uniprot.txt
      supporting_text: at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: IMP
  original_reference_id: PMID:17085480
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that DTL is required for normal cell cycle control, primarily to prevent re-replication.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the more specific G2/M-checkpoint, replication-initiation and substrate-degradation annotations better capture the role.
    supported_by:
    - reference_id: PMID:17085480
      supporting_text: dtl/cdt2 is required for normal cell cycle control, primarily to prevent rereplication
references:
- 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: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:16861906
  title: L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1
    proteolysis in response to DNA damage.
  findings:
  - statement: L2DTL/CDT2 is a conserved WD40 protein that associates with CUL4/DDB1 and PCNA and is required for CDT1 proteolysis after DNA damage.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational study identifying DTL/CDT2 as a CUL4-DDB1- and PCNA-associated factor controlling CDT1 degradation; source of the complex-membership and replication-initiation annotations.
- 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: Cdt2 is a DCAF (DDB1-CUL4-associated factor) substrate receptor required to destroy Cdt1 in S phase and after DNA damage; depletion causes rereplication and checkpoint activation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes DTL/Cdt2 as a DCAF/substrate receptor of CUL4-DDB1; source of DDB1/CUL4 interaction, complex membership and DNA-damage-response annotations. R246A DDB1-binding mutant in UniProt.
- id: PMID:17041588
  title: CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and
    regulates histone methylation.
  findings:
  - statement: CUL4-DDB1 interacts with multiple WD40-repeat proteins including L2DTL/CDT2, which regulates CDT1 proteolysis through CUL4-DDB1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the DTL-DDB1 IntAct interaction; confirms DTL as a WD40 substrate receptor of CUL4-DDB1.
- id: PMID:17085480
  title: DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint.
  findings:
  - statement: DTL promotes genomic stability by two mechanisms - as a CUL4-DDB1 component controlling CDT1 levels (preventing rereplication) and as an essential component of the early radiation-induced G2/M checkpoint (CDT1-independent).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes both the CDT1-degradation and the G2/M checkpoint roles in zebrafish and human DTL; source of checkpoint and cell-cycle annotations.
- id: PMID:17106265
  title: Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive
    hepatocellular carcinoma.
  findings:
  - statement: L2DTL localizes to the nucleus in interphase and to centrosomes through the cell cycle, is degraded in mitosis by APC/C-Cdh1, and is overexpressed in aggressive HCC.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the IDA nucleus and centrosome localizations and the APC/C-Cdh1 mitotic degradation; also documents an oncogenic overexpression phenotype (non-core).
- id: PMID:18794347
  title: PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2
    ubiquitin ligase complex.
  findings:
  - statement: PCNA promotes CRL4(Cdt2)-mediated ubiquitylation and UV-induced degradation of p21; Cdt2 is the substrate-recruiting factor and the complex ubiquitylates p21 in vivo and in vitro.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key mechanistic study of CRL4(CDT2) targeting p21 in a PCNA-dependent manner; source of polyubiquitination, transferase-activity (contributes_to), catabolism and response-to-UV annotations.
- id: PMID:20129063
  title: CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion
    DNA synthesis.
  findings:
  - statement: CRL4(Cdt2) monoubiquitinates PCNA at Lys164 in proliferating cells independent of Rad18 and is required for translesion DNA synthesis; antagonized by USP1.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; establishes the non-degradative PCNA monoubiquitination/TLS activity of CRL4(CDT2); source of monoubiquitination and translesion-synthesis annotations.
- id: PMID:21628527
  title: Selective ubiquitylation of p21 and Cdt1 by UBCH8 and UBE2G ubiquitin-conjugating
    enzymes via the CRL4Cdt2 ubiquitin ligase complex.
  findings:
  - statement: CRL4(Cdt2) uses UBCH8 to degrade p21 and Set8 and monoubiquitinate PCNA, and UBE2G to polyubiquitinate Cdt1, demonstrating substrate-selective E2 usage.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the IDA CRL4A(CDT2) complex membership; defines the E2 enzymes used by the complex for different substrates.
- id: PMID:23213251
  title: TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing
    p21.
  findings:
  - statement: TRIM39 stabilizes p21 and modulates G1/S and G2 checkpoints; DTL interacts with CDKN1A/p21.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; primarily about TRIM39 but documents the DTL-CDKN1A interaction (p21 is a CRL4(CDT2) substrate).
- id: PMID:26431207
  title: CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting
    Ubiquitination-Dependent Degradation of the Mammalian CRY1.
  findings:
  - statement: CUL4-DDB1-CDT2 ubiquitinates and degrades CRY1 (at Lys585); depletion of Cdt2/Ddb1/Pcna stabilizes CRY1 and alters circadian amplitude.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes CRY1 as a CRL4(CDT2) substrate (circadian role) and provides IDA nuclear localization and IMP ubiquitin-dependent catabolism evidence.
- id: PMID:27906959
  title: PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication
    Stress.
  findings:
  - statement: Cleaved SDE2 is degraded by CRL4(CDT2) in a cell-cycle- and DNA-damage-dependent manner; failure to degrade SDE2 impairs S-phase progression and survival.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; identifies SDE2 as a CRL4(CDT2) substrate in the replication-stress response; source of the DTL-SDE2 interaction.
- 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: High-throughput interactome; source of a bare protein binding annotation (VHL isoform).
- 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; captures the DTL-DDB1 association as a bare 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: Endogenous-tagging interactome; captures the DTL-DDB1 association as a bare protein binding annotation.
- id: PMID:36931259
  title: A central chaperone-like role for 14-3-3 proteins in human cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: 14-3-3 interactome; captures DTL-YWHAE interaction (consistent with DTL phosphorylation) as a bare protein binding annotation.
- id: file:human/DTL/DTL-deep-research-falcon.md
  title: Falcon deep research report for human DTL
  findings:
  - statement: DTL/CDT2 is the substrate-recognition (DCAF/adaptor) component of the CRL4(CDT2) CUL4-DDB1 E3 ligase that promotes substrate polyubiquitination and proteasomal degradation, central to S-phase control and genome maintenance; it is not the catalytic E3 itself.
    supporting_text: 'DTL is **not an enzyme that catalyzes a chemical transformation** (i.e., it is not the catalytic E3). Rather, its **primary biochemical function** is to act as the **adaptor/substrate receptor** that enables **CRL4-dependent ubiquitination** of selected proteins—particularly proteins that are engaged with PCNA on chromatin—thereby coupling replication/repair to proteostasis.'
  - statement: CRL4(CDT2) substrates are recruited via a PIP-degron (a PIP box plus an adjacent basic signature) on chromatin-bound PCNA, restricting ubiquitination to sites of DNA synthesis and repair synthesis.
    supporting_text: 'Canonical CRL4^CDT2 substrates contain a **PIP-degron**: a PCNA-interacting PIP motif plus an adjacent basic signature (often described as Arg/Lys residues downstream of the PIP box) that transforms PCNA binding into a degradation signal for CRL4^CDT2.'
  - statement: The best-established CRL4(CDT2) substrates are CDT1 (replication licensing), p21/CDKN1A (CDK inhibitor), and SET8/KMT5A (the sole H4K20 monomethyltransferase), the last linking DTL to chromatin regulation and replication-fork stability.
    supporting_text: SET8 is highlighted as the **sole H4K20 monomethyltransferase**, connecting DTL to chromatin regulation and replication-fork stability.
  - statement: CRL4(CDT2) activity must be tuned at stalled replication forks; DCAF14 restrains CRL4(CDT2), and its loss causes excessive turnover of CDT2 substrates (SET8, CDT1, p21) and replication-stress phenotypes rescuable by CDT2 depletion.
    supporting_text: Loss of DCAF14 caused **increased turnover of CDT2 substrates** (SET8, CDT1, p21), reduced SET8-linked chromatin marks, and replication-stress phenotypes including **nascent strand degradation** and increased DNA breakage signals, which could be rescued by **CDT2 depletion** and by inhibitors of cullin activation (MLN4924) or the proteasome (MG132).
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon synthesis (Tirado-Class 2023 Life Sci Alliance, Tang 2023 BMC Cancer, plus 2024 cancer studies) of DTL/CDT2 as the PCNA-coupled CRL4(CDT2) substrate receptor; the substrate-receptor mechanism, PIP-degron, and CDT1/p21/SET8 substrate set are fully consistent with the experimentally curated annotations and UniProt record. The DCAF14-regulation and oncogenic-substrate (SLTM, RUVBL1) claims are recent and context-specific. Citations are author-year/DOI rather than PMIDs.
- id: Reactome:R-HSA-5652005
  title: RAD18:UBE2B or RBX1:CUL4:DDB1:DTL ubiquitin ligase complex binds PCNA:POLD,POLE:RPA:RFC
    associated with damaged dsDNA
  findings: []
- id: Reactome:R-HSA-5652009
  title: RAD18:UBE2B or RBX1:CUL4:DDB1:DTL monoubiquitinates PCNA
  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: Substrate-recognition subunit (DCAF/substrate receptor) of the CRL4(CDT2)
    [DDB1-CUL4-RBX1] E3 ubiquitin ligase that recruits PCNA-bound substrates bearing a
    PIP-degron and confers substrate specificity for their polyubiquitination, coupling
    ubiquitination to chromatin-loaded PCNA at sites of DNA replication and repair.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005654
    label: nucleoplasm
  - id: GO:0005634
    label: nucleus
  in_complex:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  supported_by:
  - reference_id: file:human/DTL/DTL-uniprot.txt
    supporting_text: Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis
  - reference_id: PMID:18794347
    supporting_text: Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex.
  directly_involved_in:
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
- description: As the CRL4(CDT2) substrate receptor, drives PCNA-coupled polyubiquitination
    and proteasomal degradation of the replication-licensing factor CDT1 and the CDK
    inhibitor p21/CDKN1A (and SET8, FBH1, SDE2, CRY1), thereby preventing DNA re-replication,
    controlling replication licensing and enforcing the G2/M DNA-damage checkpoint to
    maintain genome stability.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  supported_by:
  - reference_id: file:human/DTL/DTL-uniprot.txt
    supporting_text: CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing
  - reference_id: PMID:16949367
    supporting_text: functions in Xenopus egg extracts and human cells to destroy the replication licensing protein Cdt1 in S phase and after DNA damage
  - reference_id: file:human/DTL/DTL-deep-research-falcon.md
    supporting_text: SET8 is highlighted as the **sole H4K20 monomethyltransferase**, connecting DTL to chromatin regulation and replication-fork stability.
  directly_involved_in:
  - id: GO:0030174
    label: regulation of DNA-templated DNA replication initiation
  - id: GO:0007095
    label: mitotic G2 DNA damage checkpoint signaling
- description: As the CRL4(CDT2) substrate receptor in undamaged proliferating cells,
    promotes the non-degradative monoubiquitination of PCNA at Lys164 to drive translesion
    DNA synthesis associated with replication stress.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005654
    label: nucleoplasm
  in_complex:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:20129063
    supporting_text: the CRL4(Cdt2) E3 ubiquitin ligase complex promotes PCNA monoubiqutination in proliferating cells in the absence of external DNA damage independent of Rad18
  directly_involved_in:
  - id: GO:0019985
    label: translesion synthesis
  - id: GO:0006513
    label: protein monoubiquitination
proposed_new_terms: []
suggested_questions:
- question: What structural features of the DTL WD40 propeller distinguish degradative
    polyubiquitination of PIP-degron substrates (CDT1, p21, SET8) from the non-degradative
    Lys164 monoubiquitination of PCNA, and how is the chain-type/processivity outcome selected?
- question: To what extent are DTL's centrosomal and nuclear-membrane localizations functionally
    distinct from its core chromatin-coupled CRL4(CDT2) activity, and do they reflect
    moonlighting roles or storage/relocalization pools?
- question: How is CRL4(CDT2) substrate turnover (notably of SET8) restrained at stalled
    replication forks to protect nascent DNA, and what is the mechanistic relationship between
    DCAF14 and CDT2 in tuning this activity?
suggested_experiments:
- description: Reconstitute CRL4(CDT2) ubiquitination in vitro with purified DDB1, CUL4A/B,
    RBX1 and DTL on PIP-degron substrates (CDT1, p21, SET8) loaded onto PCNA-DNA, and on
    PCNA itself, to dissect how DTL determines mono- versus poly-ubiquitination outcomes.
- description: Perform degron-tagged DTL depletion combined with quantitative proteomics
    and ubiquitinome profiling across the cell cycle and after UV/IR to define the complete
    endogenous CRL4(CDT2) substrate repertoire and its dependence on PCNA loading.