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