Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of nuclear localization, where DTL acts as the substrate receptor of the nuclear CRL4(CDT2) ligase. 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. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	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. Reason: Core biological process; directly supported by experimental degradation studies (CDT1, p21, CRY1, SDE2) and conserved across the Cdt2 family. Supporting Evidence: file:human/DTL/DTL-uniprot.txt mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2
GO:0007095 mitotic G2 DNA damage checkpoint signaling	IBA GO_REF:0000033	ACCEPT	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. Reason: Supported by IMP evidence (PMID:17085480, zebrafish and human DTL) and conserved across the family. Supporting Evidence: PMID:17085480 dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint
GO:0030674 protein-macromolecule adaptor activity	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: file:human/DTL/DTL-uniprot.txt 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 file:human/DTL/DTL-deep-research-falcon.md 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.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated electronic assignment of nuclear localization, redundant with experimental and IBA evidence. Reason: Correct core localization, redundant with IDA and IBA nucleus annotations. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005694 chromosome	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of chromosome localization from the UniProt subcellular location, consistent with the PCNA/chromatin-coupled mechanism of CRL4(CDT2). Reason: Correct; DTL acts on chromatin-bound PCNA at replication/repair sites and UniProt lists Chromosome as a subcellular location. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Chromosome.
GO:0005813 centrosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer of centrosome localization from the UniProt subcellular location; DTL is recruited to centrosomes during mitosis. Reason: Documented localization (also IDA in PMID:17106265) but peripheral to the core nuclear PCNA-coupled ubiquitination function; cytoplasmic/centrosomal pool reflects mitotic relocalization. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome.
GO:0006974 DNA damage response	IEA GO_REF:0000117	ACCEPT	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. Reason: Correct; redundant with IDA/IMP DNA damage response annotations. Supporting Evidence: file:human/DTL/DTL-uniprot.txt CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication
GO:0031965 nuclear membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer of nuclear membrane (nucleoplasmic-side peripheral membrane) localization from the UniProt subcellular location. 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. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Nucleus membrane; Peripheral membrane protein; Nucleoplasmic side.
GO:0045732 positive regulation of protein catabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA machine-learning assignment of positive regulation of protein catabolism, consistent with DTL promoting degradation of CRL4(CDT2) substrates. Reason: Correct; redundant with the IMP annotation of the same term and with the proteasome-mediated catabolism annotations. Supporting Evidence: file:human/DTL/DTL-uniprot.txt mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2
GO:0005515 protein binding	IPI PMID:17041588 CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repe...	KEEP AS NON CORE	Summary: IntAct interaction with DDB1 (Q16531), the adaptor through which DTL joins the CUL4 ligase. Bare protein binding is uninformative. 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. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Q9NZJ0; Q16531: DDB1; NbExp=6; IntAct=EBI-1176075, EBI-350322
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: High-throughput interactome interaction (with VHL isoform P40337-2). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Q9NZJ0; P40337-2: VHL; NbExp=3; IntAct=EBI-1176075, EBI-12157263
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Cell-specific interactome interaction with DDB1 (Q16531). Bare protein binding is uninformative. Reason: High-throughput interactome capturing the DTL-DDB1 association; bare protein binding is uninformative. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Q9NZJ0; Q16531: DDB1; NbExp=6; IntAct=EBI-1176075, EBI-350322
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	KEEP AS NON CORE	Summary: OpenCell endogenous-tagging interactome interaction with DDB1 (Q16531). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Q9NZJ0; Q16531: DDB1; NbExp=6; IntAct=EBI-1176075, EBI-350322
GO:0005515 protein binding	IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c...	KEEP AS NON CORE	Summary: Interaction with 14-3-3 protein YWHAE (P62258) from a 14-3-3 chaperone-network study. Bare protein binding is uninformative. Reason: Records a real DTL-YWHAE interaction (consistent with DTL phosphorylation), but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Q9NZJ0; P62258: YWHAE; NbExp=4; IntAct=EBI-1176075, EBI-356498
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway-derived general protein ubiquitination process, a parent of the specific CRL4(CDT2)-mediated ubiquitination DTL confers. Reason: Correct but generic; the specific polyubiquitination, monoubiquitination and proteasomal-catabolism annotations better capture the role. Supporting Evidence: file:human/DTL/DTL-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0030174 regulation of DNA-templated DNA replication initiation	NAS PMID:16861906 L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and...	ACCEPT	Summary: CRL4(CDT2)-dependent degradation of the licensing factor CDT1 controls replication initiation/licensing, preventing re-replication. Reason: Core biological role; DTL controls CDT1 levels to regulate replication licensing, supported experimentally across multiple studies. Supporting Evidence: file:human/DTL/DTL-uniprot.txt CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex	NAS PMID:16861906 L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and...	ACCEPT	Summary: DTL is a component of the CUL4A-RING (CRL4) ligase complex. Reason: Core complex membership; DTL/CDT2 is the substrate receptor of CRL4(CDT2), supported by IDA in multiple studies and the UniProt SUBUNIT description. Supporting Evidence: file:human/DTL/DTL-uniprot.txt 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
GO:0031465 Cul4B-RING E3 ubiquitin ligase complex	NAS PMID:16861906 L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and...	ACCEPT	Summary: DTL is also a component of the CUL4B variant of the CRL4(CDT2) ligase complex. Reason: Core complex membership; the complex uses either CUL4A or CUL4B (ComplexPortal CPX-2777 CUL4B variant), supported by IDA (PMID:18794347). Supporting Evidence: file:human/DTL/DTL-uniprot.txt at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1
GO:1901987 regulation of cell cycle phase transition	NAS PMID:16861906 L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and...	KEEP AS NON CORE	Summary: CRL4(CDT2) regulates cell-cycle phase transitions through degradation of CDT1 and p21. 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. Supporting Evidence: file:human/DTL/DTL-uniprot.txt required for cell cycle control, DNA damage response and translesion DNA synthesis
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Direct immunofluorescence (HPA) evidence for nucleoplasmic localization, consistent with DTL's nuclear site of action. Reason: IDA-supported nucleoplasm localization agrees with the core nuclear/chromatin function. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005515 protein binding	IPI PMID:23213251 TRIM39 regulates cell cycle progression and DNA damage respo...	KEEP AS NON CORE	Summary: Interaction with CDKN1A/p21 (P38936), a key CRL4(CDT2) substrate, captured in the TRIM39/p21 study. Bare protein binding is uninformative. Reason: Records the functionally meaningful DTL-p21 substrate interaction, but bare protein binding is uninformative; substrate relationship captured by catabolic-process annotations. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Interacts with CDKN1A (PubMed:23213251)
GO:0005515 protein binding	IPI PMID:26431207 CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activ...	KEEP AS NON CORE	Summary: Interaction with CRY1 (Q16526), a CRL4(CDT2) substrate in circadian regulation. Bare protein binding is uninformative. Reason: Records the real DTL-CRY1 substrate interaction, but bare protein binding is uninformative. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Interacts with CRY1 (PubMed:26431207)
GO:0005634 nucleus	IDA PMID:26431207 CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activ...	ACCEPT	Summary: Direct experimental evidence for nuclear localization of DTL in the CRY1/circadian study. Reason: IDA-supported core nuclear localization. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0006511 ubiquitin-dependent protein catabolic process	IMP PMID:26431207 CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activ...	ACCEPT	Summary: Mutant/depletion-phenotype evidence that CRL4(CDT2) drives ubiquitin-dependent degradation of CRY1 (depletion of Cdt2 stabilizes CRY1). Reason: Core biological process with experimental support; consistent with DTL's substrate-degradation role. Supporting Evidence: PMID:26431207 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
GO:0005515 protein binding	IPI PMID:27906959 PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Re...	KEEP AS NON CORE	Summary: Interaction with SDE2 (Q6IQ49), a CRL4(CDT2) substrate cleaved and degraded in the replication-stress response. Bare protein binding is uninformative. Reason: Records the real DTL-SDE2 substrate interaction, but bare protein binding is uninformative. Supporting Evidence: PMID:27906959 The cleaved SDE2 products need to be degraded by the CRL4CDT2 ubiquitin E3 ligase in a cell cycle- and DNA damage-dependent manner
GO:0007095 mitotic G2 DNA damage checkpoint signaling	IMP PMID:17085480 DTL/CDT2 is essential for both CDT1 regulation and the early...	ACCEPT	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. Reason: Core biological process with direct experimental support. Supporting Evidence: PMID:17085480 dtl/cdt2 is an essential component of the early, radiation-induced G2/M checkpoint
GO:0006974 DNA damage response	IMP PMID:16949367 A family of diverse Cul4-Ddb1-interacting proteins includes ...	ACCEPT	Summary: Mutant-phenotype evidence that Cdt2 is required to destroy Cdt1 in S phase and after DNA damage, preventing re-replication and checkpoint activation. Reason: Core biological process; depletion of Cdt2 causes rereplication and checkpoint activation. Supporting Evidence: PMID:16949367 Depletion of human Cdt2 causes rereplication and checkpoint activation.
GO:0010971 positive regulation of G2/M transition of mitotic cell cycle	IMP PMID:16949367 A family of diverse Cul4-Ddb1-interacting proteins includes ...	MARK AS OVER ANNOTATED	Summary: Mutant-phenotype evidence linking DTL to G2/M progression via prevention of re-replication and CDT1 control. 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. Supporting Evidence: PMID:16949367 Depletion of human Cdt2 causes rereplication and checkpoint activation.
GO:0045732 positive regulation of protein catabolic process	IMP PMID:16949367 A family of diverse Cul4-Ddb1-interacting proteins includes ...	ACCEPT	Summary: Mutant-phenotype evidence that DTL/Cdt2 promotes the destruction of the replication factor Cdt1. Reason: Core biological role; DTL is required for S-phase and DNA-damage-induced degradation of CDT1. Supporting Evidence: PMID:16949367 functions in Xenopus egg extracts and human cells to destroy the replication licensing protein Cdt1 in S phase and after DNA damage
GO:0005515 protein binding	IPI PMID:16949367 A family of diverse Cul4-Ddb1-interacting proteins includes ...	KEEP AS NON CORE	Summary: Interactions with DDB1 (Q16531) and CUL4A (Q13619) establishing DTL's membership in the CUL4-DDB1 ligase. Bare protein binding is uninformative. Reason: Records the core DTL-DDB1/CUL4 interactions, but bare protein binding is uninformative; captured by the complex part_of and adaptor annotations. Supporting Evidence: file:human/DTL/DTL-uniprot.txt Interacts with DDB1 (PubMed:16949367, PubMed:23478445)
GO:0080008 Cul4-RING E3 ubiquitin ligase complex	IMP PMID:16949367 A family of diverse Cul4-Ddb1-interacting proteins includes ...	ACCEPT	Summary: Mutant-phenotype evidence (DDB1-binding-dead mutant) that DTL is part of the CUL4-DDB1 (CRL4) E3 ligase complex. Reason: Core complex membership; the R246A mutant blocks DDB1 association and CRL4(DTL) ubiquitination, confirming DTL is a bona fide complex subunit. Supporting Evidence: file:human/DTL/DTL-uniprot.txt R->A: Blocks association with DDB1 and ubiquitination by DCX(DTL).
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex	IDA PMID:21628527 Selective ubiquitylation of p21 and Cdt1 by UBCH8 and UBE2G ...	ACCEPT	Summary: Direct evidence placing DTL/CDT2 in the CRL4A(CDT2) ligase that ubiquitinates p21, Cdt1 and Set8 using specific E2s (UBCH8, UBE2G). Reason: Core complex membership with direct experimental support. Supporting Evidence: PMID:21628527 CRL4(Cdt2) utilizes two different UBCs to target different substrates
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5652005	ACCEPT	Summary: Reactome curation of DTL nucleoplasm localization within the PCNA monoubiquitination (TLS) reaction. Core compartment. Reason: Correct core localization; redundant with IDA nucleoplasm evidence. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5652009	ACCEPT	Summary: Reactome curation of DTL nucleoplasm localization (PCNA monoubiquitination reaction). Core compartment. Reason: Correct core localization; redundant with IDA nucleoplasm evidence. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8952638	ACCEPT	Summary: Reactome curation of DTL nucleoplasm localization (CRL4 neddylation reaction). Core compartment. Reason: Correct core localization; redundant with IDA nucleoplasm evidence. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8952639	ACCEPT	Summary: Reactome curation of DTL nucleoplasm localization (NEDD8 binding to CRL4). Core compartment. Reason: Correct core localization; redundant with IDA nucleoplasm evidence. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8955245	ACCEPT	Summary: Reactome curation of DTL nucleoplasm localization (CAND1 binding to nuclear CRL4). Core compartment. Reason: Correct core localization; redundant with IDA nucleoplasm evidence. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8955285	ACCEPT	Summary: Reactome curation of DTL nucleoplasm localization (COMMD displacement of CAND1). Core compartment. Reason: Correct core localization; redundant with IDA nucleoplasm evidence. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8956045	ACCEPT	Summary: Reactome curation of DTL nucleoplasm localization (COP9 signalosome deneddylates nuclear CRL4). Core compartment. Reason: Correct core localization; redundant with IDA nucleoplasm evidence. Supporting Evidence: file:human/DTL/DTL-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269\|PubMed:26431207}
GO:0000209 protein polyubiquitination	TAS PMID:17085480 DTL/CDT2 is essential for both CDT1 regulation and the early...	ACCEPT	Summary: Author statement that DTL drives polyubiquitination of CRL4(CDT2) substrates (CDT1). Core ubiquitination process. Reason: Core process; CRL4(DTL) assembles polyubiquitin chains on CDT1 to target it for degradation. Supporting Evidence: file:human/DTL/DTL-uniprot.txt mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2
GO:0000209 protein polyubiquitination	IDA PMID:18794347 PCNA-dependent regulation of p21 ubiquitylation and degradat...	ACCEPT	Summary: Direct evidence that CRL4(CDT2) polyubiquitinates p21 in a PCNA-dependent manner. Core ubiquitination process. Reason: Core process with direct experimental support (in vivo and in vitro p21 ubiquitylation). Supporting Evidence: PMID:18794347 The CRL4(Cdt2) E3 ubiquitin ligase ubiquitylates p21 both in vivo and in vitro
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:18794347 PCNA-dependent regulation of p21 ubiquitylation and degradat...	ACCEPT	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. 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. Supporting Evidence: PMID:18794347 The CRL4(Cdt2) E3 ubiquitin ligase ubiquitylates p21 both in vivo and in vitro
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:20129063 CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to pro...	ACCEPT	Summary: DTL contributes to CRL4(CDT2) ubiquitin-transferase activity that monoubiquitinates PCNA at Lys164 in vitro. Reason: Correct use of contributes_to; the complex monoubiquitinates PCNA at Lys164 in vitro, an activity dependent on the CRL4(CDT2) holoenzyme. Supporting Evidence: PMID:20129063 In vitro, CRL4(Cdt2) monoubiquitinates PCNA at Lys164, the same residue that is monoubiquitinated by Rad18.
GO:0005515 protein binding	IPI PMID:18794347 PCNA-dependent regulation of p21 ubiquitylation and degradat...	KEEP AS NON CORE	Summary: Interaction with CDKN1A/p21 (P38936), the substrate ubiquitinated by CRL4(CDT2). Bare protein binding is uninformative. Reason: Records the real DTL-p21 substrate interaction, but bare protein binding is uninformative. Supporting Evidence: PMID:18794347 Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex.
GO:0005634 nucleus	IDA PMID:17106265 Role of L2DTL, cell cycle-regulated nuclear and centrosome p...	ACCEPT	Summary: Direct experimental evidence (immunostaining/fractionation) that L2DTL/DTL localizes to the nucleus in interphase. Reason: IDA-supported core nuclear localization. Supporting Evidence: PMID:17106265 L2DTL protein located to the nucleus in interphase and centered to centrosomes
GO:0005813 centrosome	IDA PMID:17106265 Role of L2DTL, cell cycle-regulated nuclear and centrosome p...	KEEP AS NON CORE	Summary: Direct experimental evidence that DTL centers to centrosomes (colocalizing with gamma-tubulin and Aurora-A) through the cell cycle. Reason: Real, directly demonstrated centrosomal localization, but peripheral to the core nuclear PCNA-coupled ubiquitination function. Supporting Evidence: PMID:17106265 centered to centrosomes, with colocalization of gamma-tubulin and Aurora-A, throughout the cell cycle, and cofractionated with gamma-tubulin
GO:0006511 ubiquitin-dependent protein catabolic process	TAS PMID:17085480 DTL/CDT2 is essential for both CDT1 regulation and the early...	ACCEPT	Summary: Author statement that DTL is required for CUL4-DDB1-mediated ubiquitin-dependent degradation of CDT1. Core process. Reason: Core biological process; redundant with IMP/IDA degradation annotations. Supporting Evidence: PMID:17085480 DTL associates with the CUL4-DDB1 E3 ubiquitin ligase and is required for CDT1 down-regulation
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:18794347 PCNA-dependent regulation of p21 ubiquitylation and degradat...	ACCEPT	Summary: Direct evidence that CRL4(CDT2) mediates ubiquitin-dependent degradation of p21 after UV. Core process. Reason: Core biological process with direct experimental support. Supporting Evidence: PMID:18794347 PCNA promotes the ubiquitylation and degradation of the CDK inhibitor p21 in cells irradiated with low dose of ultraviolet (UV)
GO:0006513 protein monoubiquitination	IDA PMID:20129063 CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to pro...	ACCEPT	Summary: Direct evidence that CRL4(CDT2) monoubiquitinates PCNA at Lys164 in proliferating cells, independent of Rad18. Core process distinct from the degradative polyubiquitination. Reason: Core process with direct experimental support; establishes a non-degradative monoubiquitination activity of CRL4(CDT2). Supporting Evidence: PMID:20129063 the CRL4(Cdt2) E3 ubiquitin ligase complex promotes PCNA monoubiqutination in proliferating cells in the absence of external DNA damage independent of Rad18
GO:0006974 DNA damage response	IDA PMID:20129063 CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to pro...	ACCEPT	Summary: Direct evidence linking CRL4(CDT2)-mediated PCNA monoubiquitination to translesion DNA synthesis, a DNA damage tolerance response. Reason: Core process; CRL4(CDT2) function is tightly tied to DNA replication-associated stress and damage tolerance. Supporting Evidence: PMID:20129063 CRL4(Cdt2) regulates PCNA-dependent TLS associated with stresses accompanying DNA replication.
GO:0009411 response to UV	IDA PMID:18794347 PCNA-dependent regulation of p21 ubiquitylation and degradat...	ACCEPT	Summary: Direct evidence that CRL4(CDT2) mediates UV-induced p21 ubiquitylation and degradation. Core process in the UV/DNA-damage response. Reason: Core process with direct experimental support; p21 degradation occurs specifically after UV irradiation. Supporting Evidence: PMID:18794347 PCNA promotes the ubiquitylation and degradation of the CDK inhibitor p21 in cells irradiated with low dose of ultraviolet (UV)
GO:0019985 translesion synthesis	IDA PMID:20129063 CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to pro...	ACCEPT	Summary: Direct evidence that CRL4(CDT2)-dependent PCNA monoubiquitination is required for translesion DNA synthesis in nondamaged cells. Core process. Reason: Core process with direct experimental support. Supporting Evidence: PMID:20129063 CRL4(Cdt2) is required for TLS in nondamaged cells via a mechanism that is dependent on PCNA monoubiquitination
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex	IDA PMID:17085480 DTL/CDT2 is essential for both CDT1 regulation and the early...	ACCEPT	Summary: Direct evidence that DTL associates with the CUL4-DDB1 (CRL4A) E3 ligase complex. Reason: Core complex membership with direct experimental support. Supporting Evidence: PMID:17085480 DTL associates with the CUL4-DDB1 E3 ubiquitin ligase
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex	IDA PMID:18794347 PCNA-dependent regulation of p21 ubiquitylation and degradat...	ACCEPT	Summary: Direct evidence that DTL/Cdt2 is part of the CRL4A(CDT2) complex that ubiquitinates p21. Reason: Core complex membership; redundant with other IDA complex annotations. Supporting Evidence: PMID:18794347 Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex.
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex	IDA PMID:20129063 CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to pro...	ACCEPT	Summary: Direct evidence that DTL/Cdt2 is part of the CRL4A(CDT2) complex that monoubiquitinates PCNA. Reason: Core complex membership; redundant with other IDA complex annotations. Supporting Evidence: PMID:20129063 the CRL4(Cdt2) E3 ubiquitin ligase complex promotes PCNA monoubiqutination
GO:0031465 Cul4B-RING E3 ubiquitin ligase complex	IDA PMID:18794347 PCNA-dependent regulation of p21 ubiquitylation and degradat...	ACCEPT	Summary: Direct evidence that DTL/Cdt2 is part of the CUL4B-variant CRL4(CDT2) complex. Reason: Core complex membership; the CRL4(CDT2) complex uses either CUL4A or CUL4B. Supporting Evidence: file:human/DTL/DTL-uniprot.txt at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1
GO:0051726 regulation of cell cycle	IMP PMID:17085480 DTL/CDT2 is essential for both CDT1 regulation and the early...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence that DTL is required for normal cell cycle control, primarily to prevent re-replication. Reason: Correct but generic; the more specific G2/M-checkpoint, replication-initiation and substrate-degradation annotations better capture the role. Supporting Evidence: PMID:17085480 dtl/cdt2 is required for normal cell cycle control, primarily to prevent rereplication

Core Functions

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:

protein-macromolecule adaptor activity

Directly Involved In:

proteasome-mediated ubiquitin-dependent protein catabolic process

Cellular Locations:

nucleoplasm nucleus

In Complex:

Cul4A-RING E3 ubiquitin ligase complex

Supporting Evidence:

file:human/DTL/DTL-uniprot.txt
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
PMID:18794347
Cdt2 functions as the substrate recruiting factor for p21 to the rest of the CRL4 ubiquitin ligase complex.

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:

protein-macromolecule adaptor activity

Directly Involved In:

regulation of DNA-templated DNA replication initiation mitotic G2 DNA damage checkpoint signaling

Cellular Locations:

nucleoplasm

In Complex:

Cul4A-RING E3 ubiquitin ligase complex

Supporting Evidence:

file:human/DTL/DTL-uniprot.txt
CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing
PMID:16949367
functions in Xenopus egg extracts and human cells to destroy the replication licensing protein Cdt1 in S phase and after DNA damage
file:human/DTL/DTL-deep-research-falcon.md
SET8 is highlighted as the **sole H4K20 monomethyltransferase**, connecting DTL to chromatin regulation and replication-fork stability.

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:

protein-macromolecule adaptor activity

Directly Involved In:

translesion synthesis protein monoubiquitination

Cellular Locations:

nucleoplasm

In Complex:

Cul4A-RING E3 ubiquitin ligase complex

Supporting Evidence:

PMID:20129063
the CRL4(Cdt2) E3 ubiquitin ligase complex promotes PCNA monoubiqutination in proliferating cells in the absence of external DNA damage independent of Rad18

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16861906

L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage.

L2DTL/CDT2 is a conserved WD40 protein that associates with CUL4/DDB1 and PCNA and is required for CDT1 proteolysis after DNA damage.

PMID:16949367

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

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.

PMID:17041588

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

CUL4-DDB1 interacts with multiple WD40-repeat proteins including L2DTL/CDT2, which regulates CDT1 proteolysis through CUL4-DDB1.

PMID:17085480

DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint.

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).

PMID:17106265

Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma.

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.

PMID:18794347

PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex.

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.

PMID:20129063

CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis.

CRL4(Cdt2) monoubiquitinates PCNA at Lys164 in proliferating cells independent of Rad18 and is required for translesion DNA synthesis; antagonized by USP1.

PMID:21628527

Selective ubiquitylation of p21 and Cdt1 by UBCH8 and UBE2G ubiquitin-conjugating enzymes via the CRL4Cdt2 ubiquitin ligase complex.

CRL4(Cdt2) uses UBCH8 to degrade p21 and Set8 and monoubiquitinate PCNA, and UBE2G to polyubiquitinate Cdt1, demonstrating substrate-selective E2 usage.

PMID:23213251

TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21.

TRIM39 stabilizes p21 and modulates G1/S and G2 checkpoints; DTL interacts with CDKN1A/p21.

PMID:26431207

CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1.

CUL4-DDB1-CDT2 ubiquitinates and degrades CRY1 (at Lys585); depletion of Cdt2/Ddb1/Pcna stabilizes CRY1 and alters circadian amplitude.

PMID:27906959

PCNA-Dependent Cleavage and Degradation of SDE2 Regulates Response to Replication Stress.

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.

PMID:32814053

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

PMID:33961781

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

PMID:35271311

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

PMID:36931259

A central chaperone-like role for 14-3-3 proteins in human cells.

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

Falcon deep research report for human DTL

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.

"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."
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.

"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."
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.

"SET8 is highlighted as the **sole H4K20 monomethyltransferase**, connecting DTL to chromatin regulation and replication-fork stability."
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.

"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)."

Reactome:R-HSA-5652005

RAD18:UBE2B or RBX1:CUL4:DDB1:DTL ubiquitin ligase complex binds PCNA:POLD,POLE:RPA:RFC associated with damaged dsDNA

Reactome:R-HSA-5652009

RAD18:UBE2B or RBX1:CUL4:DDB1:DTL monoubiquitinates PCNA

Reactome:R-HSA-8952638

AcM-UBE2M transfers NEDD8 to CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8952639

NEDD8:AcM-UBE2M binds CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8955245

CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus

Reactome:R-HSA-8955285

COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex

Reactome:R-HSA-8956045

COP9 signalosome deneddylates nuclear CRL4 E3 ubiquitin ligase complex

Suggested Experiments

Experiment: Reconstitute CRL4(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.

Experiment: 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.

Deep Research

Falcon

(DTL-deep-research-falcon.md)

Research report: Human **DTL** / **CDT2** / **DCAF2** (UniProt **Q9NZJ0**) — functional annotation Falcon Edison Scientific Literature 16 citations 2 artifacts 2026-06-13T07:16:20.938608

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000015 The document describes how DCAF14 regulates the CRL4^CDT2 (DTL/CDT2/DCAF2) E3 ubiquitin ligase to protect replication forks. Key ex (image/png)

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

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

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

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

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

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

Research report: Human DTL / CDT2 / DCAF2 (UniProt Q9NZJ0) — functional annotation

0) Target verification (mandatory)

The literature analyzed matches the UniProt target: DTL in Homo sapiens is explicitly referred to as CDT2, DCAF2, and RAMP, and is described as a DDB1–CUL4-associated factor (DCAF) that functions as the substrate receptor/adaptor in the CRL4^CDT2 (CUL4–DDB1) cullin–RING E3 ubiquitin ligase. This is consistent with UniProt’s “Denticleless protein homolog / DDB1- and CUL4-associated factor 2” description and WD40/DCAF-family expectation. (tang2023pancanceranalysisand pages 1-2, dong2023dtlisa pages 1-4)

1) Key concepts and definitions (current understanding)

1.1 DTL as a CRL4 substrate receptor (DCAF)

DTL/CDT2/DCAF2 is best understood as a substrate-recognition component that confers specificity to a CUL4–DDB1 E3 ubiquitin ligase complex (CRL4^CDT2). In this complex, DTL binds substrate proteins and promotes their polyubiquitination, leading to proteasomal degradation. This activity is central to S-phase control and genome maintenance. (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tiradoclass2024dcaf14regulatescdt2 pages 1-2)

1.2 PCNA-coupled proteolysis and the PIP-degron

A defining mechanistic concept for DTL is PCNA-coupled proteolysis. In this model, chromatin-bound PCNA (the DNA sliding clamp) acts as a recruitment/scaffolding platform that enables CRL4^CDT2 to ubiquitinate substrates specifically during DNA synthesis and repair synthesis. 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. (tiradoclass2024dcaf14regulatescdt2 pages 1-2, tiradoclass2024dcaf14regulatescdt2 pages 11-12)

Experimental support for PCNA as the in situ platform includes proximity ligation assay (PLA) evidence showing CDT2 proximity to PCNA in replicating cells. (tiradoclass2023dcaf14regulatescdt2 media 8d746bde)

1.3 What “primary function” means for DTL

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. (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tiradoclass2024dcaf14regulatescdt2 pages 1-2)

2) Molecular function: key substrates, partners, and pathways

2.1 Canonical substrates (high-confidence)

Across mechanistic and experimental descriptions, the best-established DTL/CRL4^CDT2 substrates are:

CDT1 (replication licensing factor)
p21 / CDKN1A (CDK inhibitor)
SET8 / PR-Set7 / KMT5A (histone H4K20 monomethyltransferase)

Their regulated degradation during S-phase and/or after DNA damage is repeatedly emphasized as core to DTL’s role in replication licensing control, cell-cycle progression, and genome stability. (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tiradoclass2024dcaf14regulatescdt2 pages 1-2)

SET8 is highlighted as the sole H4K20 monomethyltransferase, connecting DTL to chromatin regulation and replication-fork stability. (tiradoclass2024dcaf14regulatescdt2 pages 11-12)

2.2 Additional reported substrates/targets in recent disease-focused studies

Recent studies expand the universe of DTL-linked ubiquitination targets beyond the “canonical trio,” often in cancer contexts:

SLTM: In hepatocellular carcinoma (HCC), DTL was reported to promote ubiquitin-mediated degradation of SLTM, derepressing Notch1 and contributing to proliferation/metastasis and sorafenib resistance. (Cell Death & Disease, published Oct 2024; URL in paper metadata) (chen2024hypoxiainduceddtlpromotes pages 13-14)
RUVBL1: In breast cancer models, DTL promoted ubiquitination of RUVBL1, strengthening RUVBL1 association with RUVBL2 and β-catenin, thereby increasing transcriptional output of NHEJ pathway genes and associating with radiation resistance. (Cell Death & Disease, published Apr 2024; URL in paper metadata) (tian2024ruvbl1ubiquitinationby pages 1-2)

These findings support the view that DTL may participate in context-dependent substrate selection beyond classic PCNA/PIP-degron substrates, especially in cancer signaling and therapy response. (chen2024hypoxiainduceddtlpromotes pages 13-14, tian2024ruvbl1ubiquitinationby pages 1-2)

2.3 Cellular localization and site of action

Mechanistically, DTL function is tightly linked to chromatin-bound PCNA at replication forks, implying predominant nuclear/chromatin action during DNA replication/repair synthesis. This is directly supported by PCNA–CDT2 proximity (PLA) in replicating cells. (tiradoclass2023dcaf14regulatescdt2 media 8d746bde)

In clinical tissue, DTL has also been described with variable subcellular distribution. For example, in an HCC study, DTL was mainly cytoplasmic in paracancer tissue but elevated in both cytoplasm and nucleus in tumors, and nuclear-localized DTL associated with worse survival compared with cytoplasmic localization. (dong2023dtlisa pages 4-7)

2.4 Pathways and biological processes

In the primary literature examined here, DTL is consistently placed in pathways centered on:

DNA replication licensing and prevention of re-replication (through degradation of CDT1, p21, SET8) (tiradoclass2024dcaf14regulatescdt2 pages 1-2, tiradoclass2024dcaf14regulatescdt2 pages 11-12)
DNA damage response and genome stability, including replication stress responses (tiradoclass2024dcaf14regulatescdt2 pages 1-2, tiradoclass2024dcaf14regulatescdt2 pages 11-12)
Replication fork stability/protection, particularly through SET8-dependent mechanisms (tiradoclass2024dcaf14regulatescdt2 pages 11-12, tiradoclass2024dcaf14regulatescdt2 pages 8-11)

Supporting systems-level analyses from a pan-cancer study (Tang et al., BMC Cancer, Apr 2023; URL in metadata) found DTL-associated gene-set enrichments including cell cycle, G2M checkpoint, E2F targets, mTORC1 signaling, pyrimidine metabolism, and oocyte meiosis. (tang2023pancanceranalysisand pages 1-2)

3) Recent developments (prioritizing 2023–2024)

3.1 DCAF14 as a regulator of CRL4^CDT2 at stalled forks (Nov 2023)

Tirado-Class et al. (Life Science Alliance, Nov 2023; https://doi.org/10.26508/lsa.202302230) provide mechanistic evidence that DCAF14 restrains/controls CRL4^CDT2 activity to protect stalled replication forks. 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). (tiradoclass2024dcaf14regulatescdt2 pages 4-6, tiradoclass2024dcaf14regulatescdt2 pages 11-12)

Quantitatively, the study reports extensive imaging- and fiber-assay replication with large cell counts in some assays (e.g., analyses using ≥3,500 nuclei for one imaging assay; fiber assays quantifying ≥100 fibers), supporting robustness of phenotypes at the cellular level. (tiradoclass2024dcaf14regulatescdt2 pages 4-6, tiradoclass2024dcaf14regulatescdt2 pages 8-11)

A key figure from this paper documents both (i) CDT2–PCNA proximity and (ii) DCAF14-dependent control of CDT2 substrate stability, providing visual evidence for the PCNA platform and regulatory axis. (tiradoclass2023dcaf14regulatescdt2 media 8d746bde, tiradoclass2023dcaf14regulatescdt2 media 6181f623)

3.2 2024 cancer-mechanism studies: therapy resistance and pathway rewiring

Two 2024 studies in Cell Death & Disease provide mechanistic links between DTL activity and therapy resistance:

Breast cancer radiotherapy resistance (Apr 2024): DTL-mediated ubiquitination of RUVBL1 promoted a RUVBL1/2–β-catenin transcriptional program favoring NHEJ and attenuating TIP60-mediated chromatin acetylation associated with HR, aligning with a shift toward radiation tolerance. The study used an in vivo radiation design with 7 mice per group receiving five 3-Gy fractions (every 2 days), with tumors collected 4 hours after the final dose. (https://doi.org/10.1038/s41419-024-06651-4) (tian2024ruvbl1ubiquitinationby pages 1-2)
HCC hypoxia and sorafenib resistance (Oct 2024): DTL was reported to be transcriptionally activated by HIF-1α under hypoxia and to promote HCC proliferation/metastasis and sorafenib resistance, mechanistically via SLTM ubiquitination/degradation and subsequent Notch pathway activation. The work includes a clinical cohort of n = 209. (https://doi.org/10.1038/s41419-024-07089-4) (chen2024hypoxiainduceddtlpromotes pages 13-14)

Together, these studies suggest that DTL can participate in oncogenic programs by shaping protein stability networks beyond replication licensing alone, potentially linking DTL to transcriptional rewiring and DNA repair pathway choice in tumors. (chen2024hypoxiainduceddtlpromotes pages 13-14, tian2024ruvbl1ubiquitinationby pages 1-2)

4) Current applications and real-world implementations

4.1 Biomarker applications (diagnosis/prognosis and immune context)

A pan-cancer analysis and validation study (Tang et al., BMC Cancer, published Apr 2023; https://doi.org/10.1186/s12885-023-10755-z) concludes that DTL is broadly overexpressed in tumors (with exceptions noted) and that DTL expression correlates with prognosis and immune features across cancers; the authors frame DTL as a candidate diagnostic/prognostic and immunotherapy biomarker. (tang2023pancanceranalysisand pages 1-2)

In HCC, a 2023 study using TCGA analysis plus tissue IHC reported that higher DTL expression associates with poorer survival and that nuclear-localized DTL tracks with worse prognosis. (dong2023dtlisa pages 4-7)

4.2 Therapeutic/targeting relevance (pathway tractability)

Although no DTL-specific inhibitors were evaluated in the cited primary studies, several lines of evidence support tractability of the DTL/CRL4^CDT2 axis:

In replication-stress experiments, inhibition of cullin activation via neddylation inhibitor MLN4924 (pevonedistat) stabilized CRL4^CDT2 substrates (e.g., CDT1/p21) and reduced cullin neddylation, functioning as a pharmacologic tool to suppress CRL activity. (tiradoclass2024dcaf14regulatescdt2 pages 4-6)
Proteasome inhibition (e.g., MG132) similarly stabilized CDT2 substrates, consistent with DTL’s role in ubiquitin–proteasome-mediated proteolysis. (tiradoclass2024dcaf14regulatescdt2 pages 4-6)

From an application standpoint, these observations support a real-world paradigm: targeting upstream cullin activation, the proteasome, or potentially the PCNA-coupled recruitment interface can modulate DTL-dependent substrate turnover, which may be exploitable in tumors with DTL-driven replication stress tolerance or therapy resistance. (tiradoclass2024dcaf14regulatescdt2 pages 4-6, tian2024ruvbl1ubiquitinationby pages 1-2)

5) Expert opinions/authoritative analysis (from authoritative sources in the retrieved set)

The 2023 BMC Cancer pan-cancer analysis emphasizes DTL as a genomic-stability-linked factor that recognizes and degrades substrates as part of CRL4, and connects DTL overexpression to cell-cycle promotion and genomic instability—an interpretation consistent with DTL’s canonical replication licensing role. (tang2023pancanceranalysisand pages 1-2)
The 2023 Life Science Alliance study provides a mechanistic “expert” framing that unregulated CDT2-mediated turnover of SET8 can be deleterious under replication stress, implying that DTL activity must be tuned at stalled forks for genome stability. (tiradoclass2024dcaf14regulatescdt2 pages 11-12)

6) Relevant statistics and recent data points

6.1 HCC clinical genomics and tissue studies (2023)

Dong et al. (Current Cancer Drug Targets, published Nov 2023; https://doi.org/10.2174/1568009623666230511100246) report:

TCGA comparison: DTL mRNA 8.51 vs 4.88 in tumor vs adjacent tissue, based on 474 tumor and 50 adjacent samples. (dong2023dtlisa pages 4-7)
Survival analysis cohort with complete data: n = 363, split into 181 low and 182 high DTL expression groups; high DTL associated with poorer overall survival, with the paper reporting a large difference in a survival metric (34.97 vs 74.83) between groups. (dong2023dtlisa pages 4-7)
IHC cohort: tissue microarray with 94 HCC and 86 adjacent tissues, follow-up 4–6.7 years; DTL showed tumor-associated nuclear localization and this nuclear localization was associated with shorter survival. (dong2023dtlisa pages 1-4, dong2023dtlisa pages 4-7)

6.2 Therapy resistance model parameters (2024)

Breast cancer radiotherapy model: 7 mice per group, fractionated radiation of 3 Gy × 5 doses. (tian2024ruvbl1ubiquitinationby pages 1-2)
HCC hypoxia/sorafenib resistance study: clinical cohort n = 209. (chen2024hypoxiainduceddtlpromotes pages 13-14)

6.3 Replication-stress experimental scale (Nov 2023)

Replication fork protection work reported high-throughput cellular quantification (e.g., ≥3,500 nuclei in one imaging analysis; ≥100 fibers in fiber assays), strengthening the evidentiary weight of the fork-protection phenotype upon CDT2 dysregulation. (tiradoclass2024dcaf14regulatescdt2 pages 4-6, tiradoclass2024dcaf14regulatescdt2 pages 8-11)

7) Functional annotation summary (recommended)

Aspect	Findings
identity/domains	- Human DTL corresponds to UniProt Q9NZJ0 and is explicitly identified in recent literature as CDT2/DCAF2/RAMP, a DDB1- and CUL4-associated factor (DCAF) within the CRL4 system (tang2023pancanceranalysisand pages 1-2, dong2023dtlisa pages 1-4) - It belongs to the WD40/DCAF substrate-receptor class, consistent with the UniProt WD-repeat family/domain assignment and literature describing DTL/CDT2 as a WD40-containing CRL4 receptor (tang2023pancanceranalysisand pages 1-2, gao2024hypoxiainduceddtlpromotes pages 13-16)
complex	- DTL functions as the substrate receptor/adaptor of the CRL4^CDT2 E3 ubiquitin ligase built around CUL4–DDB1 (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tiradoclass2024dcaf14regulatescdt2 pages 1-2) - This complex mediates ubiquitin-dependent proteolysis of replication- and repair-linked proteins to preserve genome stability (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tang2023pancanceranalysisand pages 1-2)
mechanism	- Core mechanism is PCNA-coupled proteolysis: DTL recognizes substrates engaged with chromatin-bound PCNA and promotes their ubiquitination and proteasomal degradation (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tiradoclass2024dcaf14regulatescdt2 pages 1-2) - Canonical substrates carry a PIP-degron (PIP box plus basic residue motif), which binds PCNA with higher affinity than standard PIP motifs and creates a degron for CRL4^CDT2 (tiradoclass2024dcaf14regulatescdt2 pages 1-2, tiradoclass2024dcaf14regulatescdt2 pages 11-12) - Image-based PLA data support CDT2 proximity to PCNA at replication forks, reinforcing PCNA as the recruitment platform (tiradoclass2023dcaf14regulatescdt2 media 8d746bde)
key substrates	- Best-established substrates are CDT1, p21/CDKN1A, and SET8/PR-Set7/KMT5A (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tiradoclass2024dcaf14regulatescdt2 pages 1-2) - Additional reported substrates/targets in disease contexts include E2F1, PDCD4, SLTM, and RUVBL1 (chen2024hypoxiainduceddtlpromotes pages 13-14, tian2024ruvbl1ubiquitinationby pages 1-2) - SET8 turnover is especially important because SET8 is the sole H4K20 monomethyltransferase, linking DTL to chromatin state and fork protection (tiradoclass2024dcaf14regulatescdt2 pages 11-12)
localization	- DTL acts mainly in the nucleus/on chromatin at replication forks through association with PCNA during DNA synthesis and repair synthesis (tiradoclass2024dcaf14regulatescdt2 pages 14-15, tiradoclass2023dcaf14regulatescdt2 media 8d746bde) - In HCC tissue, DTL protein was reported as mainly cytoplasmic in paracancer tissue but elevated in both cytoplasm and nucleus in tumors; stronger nuclear localization associated with worse survival (dong2023dtlisa pages 4-7)
pathways/biological processes	- Principal functions cluster in DNA replication licensing, S-phase progression, DNA damage responses, replication stress tolerance, and genome stability maintenance (tiradoclass2024dcaf14regulatescdt2 pages 1-2, tang2023pancanceranalysisand pages 1-2) - By degrading CDT1, p21, and SET8, DTL helps prevent re-replication, coordinate checkpoint/cell-cycle transitions, and regulate chromatin during replication (tiradoclass2024dcaf14regulatescdt2 pages 1-2, tiradoclass2024dcaf14regulatescdt2 pages 11-12) - GSEA/pan-cancer analyses linked DTL to cell cycle, G2/M checkpoint, E2F targets, mTORC1 signaling, oocyte meiosis, and pyrimidine metabolism (tang2023pancanceranalysisand pages 1-2)
recent 2023-2024 developments	- 2023: DCAF14 was shown to restrain CRL4^CDT2 activity; loss of DCAF14 causes excessive degradation of SET8/p21/CDT1 and fork collapse under replication stress (tiradoclass2024dcaf14regulatescdt2 pages 4-6, tiradoclass2024dcaf14regulatescdt2 pages 11-12) - 2024: In breast cancer, DTL-mediated RUVBL1 ubiquitination promoted a shift toward NHEJ gene transcription and radiation resistance (tian2024ruvbl1ubiquitinationby pages 1-2) - 2024: In HCC, hypoxia/HIF-1α-induced DTL promoted proliferation, metastasis, and sorafenib resistance via SLTM degradation and Notch activation (chen2024hypoxiainduceddtlpromotes pages 13-14)
disease/clinical relevance	- DTL is repeatedly reported as overexpressed across many tumor types and associated with poor prognosis, proliferation, genomic instability, and aggressive disease biology (tang2023pancanceranalysisand pages 1-2, chen2024hypoxiainduceddtlpromotes pages 13-14) - HCC-focused studies linked high DTL expression to poorer overall survival and to cell-cycle/proliferative programs (dong2023dtlisa pages 4-7, dong2023dtlisa pages 1-4) - Pan-cancer analyses also associate DTL with immune infiltration and possible relevance to immunotherapy response (tang2023pancanceranalysisand pages 1-2)
actionable/therapeutic angles	- Cullin/neddylation inhibition (e.g., MLN4924/pevonedistat) stabilizes CRL4^CDT2 substrates and is widely used experimentally to blunt DTL-dependent proteolysis, supporting pathway tractability (tiradoclass2024dcaf14regulatescdt2 pages 4-6, tiradoclass2024dcaf14regulatescdt2 pages 11-12) - Recent cancer studies propose DTL as a candidate biomarker and possible therapeutic target in HCC and breast cancer, including potential radiosensitization by targeting the DTL–RUVBL1/2–β-catenin axis (chen2024hypoxiainduceddtlpromotes pages 13-14, tian2024ruvbl1ubiquitinationby pages 1-2) - Indirect strategies include modulating upstream regulators such as HIF-1α or E2F1, or targeting the PCNA-coupled degradation interface (chen2024hypoxiainduceddtlpromotes pages 13-14, dong2023dtlisa pages 1-4)
key quantitative stats	- HCC TCGA dataset: DTL mRNA reported as 8.51 vs 4.88 in tumor vs adjacent tissue, from 474 cancer and 50 adjacent samples; survival analysis used n=363 patients split into 181 low and 182 high DTL groups (dong2023dtlisa pages 4-7) - HCC protein cohort: tissue microarray included 94 HCC and 86 adjacent specimens; follow-up was 4–6.7 years (dong2023dtlisa pages 1-4) - 2024 HCC study: clinical cohort size n=209; 2024 breast cancer RT study: 7 mice/group, five 3 Gy fractions, tumors collected 4 h after the final irradiation (chen2024hypoxiainduceddtlpromotes pages 13-14, tian2024ruvbl1ubiquitinationby pages 1-2)

Table: This table summarizes verified identity, mechanism, substrates, localization, pathways, and recent disease-relevant findings for human DTL/CDT2/DCAF2. It is useful as a compact evidence map for functional annotation and translational interpretation.

8) Notes on evidence gaps

Some clinically oriented papers in the retrieved set describe DTL as a biomarker but (in the accessible extracted pages) do not provide hazard ratios, ROC AUC values, or detailed multivariable model coefficients; therefore, such statistics cannot be reported here without additional full-text extraction beyond the available context. (tang2023pancanceranalysisand pages 1-2)

9) Key references (recent prioritized; publication date + URL)

Tirado-Class N. et al. “DCAF14 regulates CDT2 to promote SET8-dependent replication fork protection.” Life Science Alliance (Nov 2023). https://doi.org/10.26508/lsa.202302230 (tiradoclass2024dcaf14regulatescdt2 pages 4-6)
Tang Y. et al. “Pan-cancer analysis and experimental validation of DTL as a potential diagnosis, prognosis and immunotherapy biomarker.” BMC Cancer (Apr 2023). https://doi.org/10.1186/s12885-023-10755-z (tang2023pancanceranalysisand pages 1-2)
Tian J. et al. “RUVBL1 ubiquitination by DTL … enhances radiation resistance in breast cancer.” Cell Death & Disease (Apr 2024). https://doi.org/10.1038/s41419-024-06651-4 (tian2024ruvbl1ubiquitinationby pages 1-2)
Chen Z-X. et al. “Hypoxia-induced DTL … sorafenib resistance … Notch pathway activation.” Cell Death & Disease (Oct 2024). https://doi.org/10.1038/s41419-024-07089-4 (chen2024hypoxiainduceddtlpromotes pages 13-14)
Dong R. et al. “DTL is a Novel Downstream Gene of E2F1 that Promotes the Progression of Hepatocellular Carcinoma.” Current Cancer Drug Targets (Nov 2023). https://doi.org/10.2174/1568009623666230511100246 (dong2023dtlisa pages 4-7)

10) OpenTargets snapshot (database context; not a substitute for mechanistic literature)

OpenTargets lists disease associations for DTL with modest association scores across several indications (e.g., neurodegenerative disease, diabetes mellitus/type 2 diabetes, gout, migraine), supported by limited evidence items and PubMed links; these associations should be interpreted as hypothesis-generating rather than definitive functional annotation. (OpenTargets Search: -DTL)

References

(tang2023pancanceranalysisand pages 1-2): Yumei Tang, Ye Lei, Peng Gao, Junting Jia, Huijun Du, Qitong Wang, Zhixin Yan, Chen Zhang, Guojun Liang, Yanfeng Wang, Weijun Ma, Nianzeng Xing, Le Cheng, and Laifeng Ren. Pan-cancer analysis and experimental validation of dtl as a potential diagnosis, prognosis and immunotherapy biomarker. BMC Cancer, Apr 2023. URL: https://doi.org/10.1186/s12885-023-10755-z, doi:10.1186/s12885-023-10755-z. This article has 17 citations and is from a peer-reviewed journal.
(dong2023dtlisa pages 1-4): Ruiqiang Dong, Danhua Zhang, Baowei Han, Lingxue Xu, Danfeng Zhang, Zhenguo Cheng, and Xinguang Qiu. Dtl is a novel downstream gene of e2f1 that promotes the progression of hepatocellular carcinoma. Current Cancer Drug Targets, 23:817-828, Nov 2023. URL: https://doi.org/10.2174/1568009623666230511100246, doi:10.2174/1568009623666230511100246. This article has 4 citations and is from a peer-reviewed journal.
(tiradoclass2024dcaf14regulatescdt2 pages 14-15): Neysha Tirado-Class, Caitlin Hathaway, Anthony Nelligan, Thuan Nguyen, and Huzefa Dungrawala. Dcaf14 regulates cdt2 to promote set8-dependent replication fork protection. Life Science Alliance, 7:e202302230, Nov 2023. URL: https://doi.org/10.26508/lsa.202302230, doi:10.26508/lsa.202302230. This article has 1 citations and is from a peer-reviewed journal.
(tiradoclass2024dcaf14regulatescdt2 pages 1-2): Neysha Tirado-Class, Caitlin Hathaway, Anthony Nelligan, Thuan Nguyen, and Huzefa Dungrawala. Dcaf14 regulates cdt2 to promote set8-dependent replication fork protection. Life Science Alliance, 7:e202302230, Nov 2023. URL: https://doi.org/10.26508/lsa.202302230, doi:10.26508/lsa.202302230. This article has 1 citations and is from a peer-reviewed journal.
(tiradoclass2024dcaf14regulatescdt2 pages 11-12): Neysha Tirado-Class, Caitlin Hathaway, Anthony Nelligan, Thuan Nguyen, and Huzefa Dungrawala. Dcaf14 regulates cdt2 to promote set8-dependent replication fork protection. Life Science Alliance, 7:e202302230, Nov 2023. URL: https://doi.org/10.26508/lsa.202302230, doi:10.26508/lsa.202302230. This article has 1 citations and is from a peer-reviewed journal.
(tiradoclass2023dcaf14regulatescdt2 media 8d746bde): Neysha Tirado-Class, Caitlin Hathaway, Anthony Nelligan, Thuan Nguyen, and Huzefa Dungrawala. Dcaf14 regulates cdt2 to promote set8-dependent replication fork protection. Life Science Alliance, 7:e202302230, Nov 2023. URL: https://doi.org/10.26508/lsa.202302230, doi:10.26508/lsa.202302230. This article has 1 citations and is from a peer-reviewed journal.
(chen2024hypoxiainduceddtlpromotes pages 13-14): Zi-Xiong Chen, Mao-Yuan Mu, Guang Yang, Han Qi, Xiao-Bo Fu, Gui-Song Wang, Wei-Wei Jiang, Bi-Jun Huang, and Fei Gao. Hypoxia-induced dtl promotes the proliferation, metastasis, and sorafenib resistance of hepatocellular carcinoma through ubiquitin-mediated degradation of sltm and subsequent notch pathway activation. Cell Death & Disease, Oct 2024. URL: https://doi.org/10.1038/s41419-024-07089-4, doi:10.1038/s41419-024-07089-4. This article has 19 citations and is from a peer-reviewed journal.
(tian2024ruvbl1ubiquitinationby pages 1-2): Jie Tian, Mingxin Wen, Peng Gao, Maoxiao Feng, and Guangwei Wei. Ruvbl1 ubiquitination by dtl promotes ruvbl1/2-β-catenin-mediated transcriptional regulation of nhej pathway and enhances radiation resistance in breast cancer. Cell Death & Disease, Apr 2024. URL: https://doi.org/10.1038/s41419-024-06651-4, doi:10.1038/s41419-024-06651-4. This article has 19 citations and is from a peer-reviewed journal.
(dong2023dtlisa pages 4-7): Ruiqiang Dong, Danhua Zhang, Baowei Han, Lingxue Xu, Danfeng Zhang, Zhenguo Cheng, and Xinguang Qiu. Dtl is a novel downstream gene of e2f1 that promotes the progression of hepatocellular carcinoma. Current Cancer Drug Targets, 23:817-828, Nov 2023. URL: https://doi.org/10.2174/1568009623666230511100246, doi:10.2174/1568009623666230511100246. This article has 4 citations and is from a peer-reviewed journal.
(tiradoclass2024dcaf14regulatescdt2 pages 8-11): Neysha Tirado-Class, Caitlin Hathaway, Anthony Nelligan, Thuan Nguyen, and Huzefa Dungrawala. Dcaf14 regulates cdt2 to promote set8-dependent replication fork protection. Life Science Alliance, 7:e202302230, Nov 2023. URL: https://doi.org/10.26508/lsa.202302230, doi:10.26508/lsa.202302230. This article has 1 citations and is from a peer-reviewed journal.
(tiradoclass2024dcaf14regulatescdt2 pages 4-6): Neysha Tirado-Class, Caitlin Hathaway, Anthony Nelligan, Thuan Nguyen, and Huzefa Dungrawala. Dcaf14 regulates cdt2 to promote set8-dependent replication fork protection. Life Science Alliance, 7:e202302230, Nov 2023. URL: https://doi.org/10.26508/lsa.202302230, doi:10.26508/lsa.202302230. This article has 1 citations and is from a peer-reviewed journal.
(tiradoclass2023dcaf14regulatescdt2 media 6181f623): Neysha Tirado-Class, Caitlin Hathaway, Anthony Nelligan, Thuan Nguyen, and Huzefa Dungrawala. Dcaf14 regulates cdt2 to promote set8-dependent replication fork protection. Life Science Alliance, 7:e202302230, Nov 2023. URL: https://doi.org/10.26508/lsa.202302230, doi:10.26508/lsa.202302230. This article has 1 citations and is from a peer-reviewed journal.
(gao2024hypoxiainduceddtlpromotes pages 13-16): Fei Gao, Zi-Xiong Chen, Mao-Yuan Mu, Guang Yang, Han Qi, Xiao-Bo Fu, Gui-Song Wang, Wei-Wei Jiang, and Bi-Jun Huang. Hypoxia-induced dtl promotes the proliferation, metastasis, and sorafenib resistance of hepatocellular carcinoma through notch signaling pathway. Unknown journal, Jan 2024. URL: https://doi.org/10.21203/rs.3.rs-3691309/v1, doi:10.21203/rs.3.rs-3691309/v1.
(OpenTargets Search: -DTL): Open Targets Query (-DTL, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

Edison artifact artifact-00

Citations

chen2024hypoxiainduceddtlpromotes pages 13-14
dong2023dtlisa pages 4-7
tang2023pancanceranalysisand pages 1-2
dong2023dtlisa pages 1-4
gao2024hypoxiainduceddtlpromotes pages 13-16
https://doi.org/10.26508/lsa.202302230
https://doi.org/10.1038/s41419-024-06651-4
https://doi.org/10.1038/s41419-024-07089-4
https://doi.org/10.1186/s12885-023-10755-z
https://doi.org/10.2174/1568009623666230511100246
https://doi.org/10.1186/s12885-023-10755-z,
https://doi.org/10.2174/1568009623666230511100246,
https://doi.org/10.26508/lsa.202302230,
https://doi.org/10.1038/s41419-024-07089-4,
https://doi.org/10.1038/s41419-024-06651-4,
https://doi.org/10.21203/rs.3.rs-3691309/v1,

📚 Additional Documentation

Pn Notes

(DTL-pn-notes.md)

DTL PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9NZJ0
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

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

Deep Research Files

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

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 41; KEEP_AS_NON_CORE: 16; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

Consistency: Consistent on biology — DTL/CDT2 is the DCAF substrate receptor of CRL4(CDT2), recruiting PCNA-bound PIP-degron substrates (CDT1, p21, SET8, FBH1, SDE2). Divergence only in MF vocabulary: review uses GO:0030674 (protein-macromolecule adaptor activity, ACCEPTed from GOA IBA) for all three core functions; PN projects GO:1990756.
PN story / NEW pressure: PN projects GO:1990756 as "more_specific_than_existing_goa." GOA already has GO:0030674 (enables, IBA) and GO:0004842 (contributes_to) — confirmed in goa.tsv; GO:1990756 is NOT in GOA. GO:1990756 (verified real; F-box/BTB receptor MF) is indeed more specific than the generic GO:0030674 for a CRL substrate receptor. Verdict: defensible ADD (more specific), but the reviewer deliberately preferred GO:0030674 as the receptor MF; this is a vocabulary judgment, not a substantive disagreement.
Evidence alignment: PN row lists no references; the review is well-evidenced (PMID:16949367 Cdt1 destruction; 18794347 p21 recruitment; 17085480 G2/M checkpoint IMP; 20129063 PCNA K164 monoubiquitination). No conflict; PN under-cites.
Verdict: Consistent; PN GO:1990756 is correctly categorized and a defensible more-specific add over the review's GO:0030674. Recommended edits: [YAML] optionally add/swap GO:1990756 as the DCAF substrate-receptor MF (more specific than GO:0030674), aligning with the PN projection.

Full Consistency Review

UniProt: Q9NZJ0 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor|WD40|other ; PN-node mapping: group "Cul4A/Cul4B substrate receptor"=mapped, ok_for_propagation, GO:1990756 (substrate-adaptor MF); subtype/type=no_mapping; projected GO:1990756 goa_status=more_specific_than_existing_goa.
Consistency: Consistent on biology — DTL/CDT2 is the DCAF substrate receptor of CRL4(CDT2), recruiting PCNA-bound PIP-degron substrates (CDT1, p21, SET8, FBH1, SDE2). Divergence only in MF vocabulary: review uses GO:0030674 (protein-macromolecule adaptor activity, ACCEPTed from GOA IBA) for all three core functions; PN projects GO:1990756.
PN story / NEW pressure: PN projects GO:1990756 as "more_specific_than_existing_goa." GOA already has GO:0030674 (enables, IBA) and GO:0004842 (contributes_to) — confirmed in goa.tsv; GO:1990756 is NOT in GOA. GO:1990756 (verified real; F-box/BTB receptor MF) is indeed more specific than the generic GO:0030674 for a CRL substrate receptor. Verdict: defensible ADD (more specific), but the reviewer deliberately preferred GO:0030674 as the receptor MF; this is a vocabulary judgment, not a substantive disagreement.
Mapping strategy: Correct category — DTL is a genuine DCAF substrate receptor, so GO:1990756 (receptor) is well placed (contrast DDB1, which is scaffold). Node status/scope appropriate; narrower than existing generic GOA.
Evidence alignment: PN row lists no references; the review is well-evidenced (PMID:16949367 Cdt1 destruction; 18794347 p21 recruitment; 17085480 G2/M checkpoint IMP; 20129063 PCNA K164 monoubiquitination). No conflict; PN under-cites.
Verdict: Consistent; PN GO:1990756 is correctly categorized and a defensible more-specific add over the review's GO:0030674. Recommended edits: [YAML] optionally add/swap GO:1990756 as the DCAF substrate-receptor MF (more specific than GO:0030674), aligning with the PN projection.

PN Dossier Context

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

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

UniProt: Q9NZJ0
In branches: UPS
Signature domains: (none)
Auxiliary domains: IPR001680
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor|WD40|other
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor|WD40
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate receptor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
  rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

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

Note

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

📄 View Raw YAML

id: 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.

DTL

Gene Description

Existing Annotations Review

Core Functions

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human DTL / CDT2 / DCAF2 (UniProt Q9NZJ0) — functional annotation

0) Target verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 DTL as a CRL4 substrate receptor (DCAF)

1.2 PCNA-coupled proteolysis and the PIP-degron

1.3 What “primary function” means for DTL

2) Molecular function: key substrates, partners, and pathways

2.1 Canonical substrates (high-confidence)

2.2 Additional reported substrates/targets in recent disease-focused studies

2.3 Cellular localization and site of action

2.4 Pathways and biological processes

3) Recent developments (prioritizing 2023–2024)

3.1 DCAF14 as a regulator of CRL4^CDT2 at stalled forks (Nov 2023)

3.2 2024 cancer-mechanism studies: therapy resistance and pathway rewiring

4) Current applications and real-world implementations

4.1 Biomarker applications (diagnosis/prognosis and immune context)

4.2 Therapeutic/targeting relevance (pathway tractability)

5) Expert opinions/authoritative analysis (from authoritative sources in the retrieved set)

6) Relevant statistics and recent data points

6.1 HCC clinical genomics and tissue studies (2023)

6.2 Therapy resistance model parameters (2024)

6.3 Replication-stress experimental scale (Nov 2023)

7) Functional annotation summary (recommended)

8) Notes on evidence gaps

9) Key references (recent prioritized; publication date + URL)

10) OpenTargets snapshot (database context; not a substitute for mechanistic literature)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

DTL PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

Projected GO annotations (1)

Note

📄 View Raw YAML