Affinage

DTL

Denticleless protein homolog · UniProt Q9NZJ0

Length
730 aa
Mass
79.5 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DTL (also known as CDT2 or DCAF2) is the substrate-recognition subunit of the CRL4^CDT2 E3 ubiquitin ligase, serving as a central regulator of DNA replication licensing, DNA damage responses, and cell cycle checkpoints. DTL bridges the CUL4–DDB1 catalytic core to substrates bearing a PIP degron—a specialized PCNA-interaction motif containing TD and downstream basic residues—on chromatin-loaded PCNA, thereby directing ubiquitylation and proteasomal degradation of CDT1, p21, SET8/PR-Set7, CHK1, XPG, FBH1, CRY1, PDCD4, DNA-PKcs, and RUVBL1 during S phase, after DNA damage, and in circadian regulation (PMID:16949367, PMID:20932472, PMID:21143559, PMID:23677613, PMID:26431207, PMID:31409387, PMID:33627782, PMID:38609375). DTL binds PCNA directly through a high-affinity C-terminal PIP box (~100-fold greater than substrate PIP boxes), and its own abundance is tightly controlled by SCF^FBXO11-mediated degradation—antagonized by 14-3-3 binding to phospho-Thr464—and by CRL4^DDB2-dependent ubiquitylation (PMID:30623174, PMID:23478441, PMID:25154416, PMID:33557942). Beyond replication control, DTL functions in a CDT1-independent G2/M checkpoint, regulates NIK-dependent IL-23 signaling in dendritic cells, and is essential for early embryonic development, with maternal DTL preventing DNA re-replication in the first zygotic cell cycle (PMID:17085480, PMID:30018073, PMID:28818995, PMID:17107960).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Identification of DTL as the substrate receptor of the CUL4–DDB1 complex that recruits CDT1 via PCNA for S-phase and damage-induced degradation established the core replication-licensing safeguard mechanism.

    Evidence Affinity chromatography/mass spectrometry, reciprocal Co-IP, Xenopus egg extract depletion-reconstitution, siRNA with rereplication readout across multiple labs

    PMID:16252005 PMID:16861906 PMID:16949367 PMID:17039252

    Open questions at the time
    • Structural basis of DTL–DDB1–PCNA ternary complex unknown at this stage
    • Full substrate repertoire beyond CDT1 and Spd1 not defined
    • Mechanism by which DTL distinguishes CDT1 from other PCNA-binding proteins not elucidated
  2. 2006 High

    Demonstration that DTL has a CDT1-independent role in the early G2/M checkpoint and is essential for embryonic viability revealed that DTL functions extend beyond replication licensing.

    Evidence Zebrafish forward genetic screen with genetic epistasis (cdt1 reduction in dtl mutant), mouse L2dtl knockout with embryonic arrest at 4–8-cell stage, siRNA in human cells

    PMID:17085480 PMID:17107960

    Open questions at the time
    • Identity of the CDT1-independent G2/M checkpoint substrate remains unknown
    • Mechanism linking DTL loss to mitotic catastrophe not molecularly resolved
  3. 2008 Medium

    Characterization of DTL cell-cycle-dependent localization and its mitotic phosphorylation by Aurora B provided the first evidence for post-translational regulation of DTL itself.

    Evidence Immunocytochemistry in synchronized cells, in vitro kinase assay with AURKB, siRNA knockdown

    PMID:18542055

    Open questions at the time
    • Aurora B–DTL interaction shown only by in vitro kinase assay; no in vivo phosphorylation site mapping
    • Functional consequence of Aurora B phosphorylation on DTL activity not determined
    • Centrosomal localization reported by different lab (PMID:17106265) but functional relevance at centrosomes unresolved
  4. 2010 High

    Discovery that CRL4^CDT2 monoubiquitinates PCNA at K164 for translesion synthesis and targets SET8/PR-Set7 via its PIP degron expanded the substrate repertoire from replication licensing to chromatin regulation and DNA damage tolerance.

    Evidence In vitro reconstitution with purified CRL4^CDT2, K164R PCNA mutagenesis, siRNA plus chromatin fractionation, PIP-degron mutant Set8 expression

    PMID:20129063 PMID:20932472 PMID:21035370 PMID:21220508

    Open questions at the time
    • How CRL4^CDT2 selects between monoubiquitination of PCNA and polyubiquitination of substrates unclear
    • Relative contributions of CRL4^CDT2 versus Rad18 to PCNA monoubiquitination in different contexts not fully resolved
  5. 2011 High

    Definition of the PIP degron code—TD motif plus downstream basic residues on PCNA—as the universal recognition element for CRL4^CDT2 substrates unified the substrate-recognition mechanism and enabled prediction of new targets.

    Evidence Systematic mutagenesis of chimeric Cdt1/ligase I constructs, in vivo degradation assays, electrostatic surface modeling

    PMID:21143559 PMID:21828267

    Open questions at the time
    • No crystal structure of DTL WD40 domain engaging PIP degron–PCNA complex
    • How substrates like CHK1 that lack canonical PIP degrons are recognized not explained by this model
  6. 2011 Medium

    Linking CRL4^CDT2 to mismatch repair through PCNA–MSH6–Cdt2 complex formation on alkylation-damaged chromatin and to Drosophila E2F1 degradation in endocycles demonstrated tissue-specific and damage-type-specific deployment of the complex.

    Evidence siRNA, Co-IP, chromatin fractionation for MMR; Drosophila genetic epistasis and computational modeling for endocycles

    PMID:21725088 PMID:22037307

    Open questions at the time
    • Whether E2F1 contains a canonical PIP degron not determined
    • Relationship between MSH2/MSH6 and CRL4^CDT2 substrate engagement mechanistically unresolved
  7. 2013 High

    Discovery that SCF^FBXO11 targets CDT2 itself for degradation, with CDK-mediated phosphorylation at Thr464 paradoxically inhibiting FBXO11 recognition, established a reciprocal E3 ligase circuit controlling CDT2 abundance.

    Evidence AP-MS, Co-IP, phosphorylation site mutagenesis, proteasome inhibitor experiments; two independent labs published concurrently

    PMID:23478441 PMID:23478445

    Open questions at the time
    • Structural basis of FBXO11–CDT2 interaction unknown
    • Which CDK(s) phosphorylate Thr464 in vivo not definitively assigned
  8. 2014 Medium

    Identification of 14-3-3 proteins as protective shields of phospho-Thr464 CDT2 against FBXO11-mediated degradation completed the regulatory circuit controlling CDT2 protein stability across the cell cycle.

    Evidence Co-IP, phospho-mimicking mutagenesis, in vivo ubiquitination assay, siRNA knockdown of 14-3-3γ

    PMID:25154416

    Open questions at the time
    • Which 14-3-3 isoform is physiologically dominant not resolved
    • Whether 14-3-3 binding affects CDT2 E3 ligase activity toward substrates not tested
  9. 2015 Medium

    Extension of the CRL4^CDT2 substrate list to include XPG (coordinating NER gap-filling) and CRY1 (modulating circadian amplitude) demonstrated roles beyond canonical cell cycle control.

    Evidence Proximity ligation assay and micropore UV irradiation for XPG; in vitro ubiquitination and K585A mutagenesis with bioluminescence circadian reporter for CRY1

    PMID:25483071 PMID:26431207

    Open questions at the time
    • Whether CRY1 degradation by CRL4^CDT2 is PCNA-dependent on chromatin not fully resolved
    • Physiological relevance of CRY1 regulation by CRL4^CDT2 versus other CRY E3 ligases not compared
  10. 2018 High

    Crystal structures of the Cdt2 PIP box bound to PCNA revealed ~100-fold higher affinity than substrate PIP boxes, explaining how the E3 ligase is stably anchored to PCNA while substrates cycle through, and maternal DTL was shown essential for the first zygotic division.

    Evidence X-ray crystallography of PCNA–Cdt2PIP and PCNA–Cdt1PIP, ITC, mutagenesis with in vivo degradation assay; oocyte-specific Dcaf2 KO in mice

    PMID:28818995 PMID:30623174

    Open questions at the time
    • No structure of full-length DTL WD40 domain in complex with PCNA and substrate PIP degron
    • How the trimeric PCNA ring coordinates simultaneous binding of three Cdt2 PIP peptides with substrate recognition unknown
  11. 2018 High

    Conditional knockout of Dcaf2 in dendritic cells revealed a non-canonical role for CRL4^CDT2 in degrading NIK to suppress non-canonical NF-κB signaling and IL-23 production, linking DTL to immune regulation and autoimmunity.

    Evidence DC-conditional Dcaf2 KO mice, in vivo ubiquitination assay, transcriptomics, psoriasis model

    PMID:30018073

    Open questions at the time
    • Whether NIK is a direct PIP-degron substrate of CRL4^CDT2 or an indirect target not established
    • Relevance to human autoimmune disease not demonstrated
  12. 2019 Medium

    Identification of PDCD4 tumor suppressor as a direct DTL ubiquitylation substrate linked CRL4^CDT2 to tumor suppressor turnover and oncogenic cell migration.

    Evidence AP-MS, Co-IP, in vitro ubiquitination assay, siRNA rescue experiments

    PMID:31409387

    Open questions at the time
    • Whether PDCD4 degradation by DTL is PCNA- and PIP-degron-dependent not tested
    • Contribution relative to SCF^βTrCP-mediated PDCD4 degradation not compared
  13. 2021 Medium

    Discovery that CRL4^DDB2 ubiquitylates CDT2 independently of PCNA, alongside identification of DNA-PKcs as a CRL4^CDT2 substrate affecting NHEJ, revealed a second E3 ligase controlling CDT2 levels and further connected DTL to DSB repair.

    Evidence Co-IP, in vivo ubiquitination assay, PIP-box mutagenesis for DDB2; NHEJ reporter assay, comet assay, γH2AX for DNA-PKcs

    PMID:33557942 PMID:33627782

    Open questions at the time
    • How CRL4^DDB2 and SCF^FBXO11 coordinate DTL turnover in different cell cycle phases unknown
    • Whether DNA-PKcs degradation by DTL occurs through a PIP-degron mechanism not determined
  14. 2024 Medium

    DTL-dependent ubiquitination of RUVBL1 was shown to switch its binding partner from TIP60 to RUVBL2/β-catenin, redirecting DSB repair from HR to NHEJ and conferring radiation resistance, revealing a substrate-level mechanism by which DTL modulates DNA repair pathway choice.

    Evidence Co-IP, in vivo ubiquitination assay, ChIP, siRNA knockdown, in vivo tumor irradiation model

    PMID:38609375

    Open questions at the time
    • Whether RUVBL1 ubiquitination by DTL is PCNA-dependent not tested
    • Structural basis for how ubiquitination of RUVBL1 alters partner selectivity unknown
    • Single lab finding; independent replication needed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structural model of the full CRL4^CDT2 complex engaged with a PIP-degron substrate on PCNA-loaded DNA is lacking, and the mechanism by which DTL recognizes PCNA-independent substrates such as CHK1 and NIK remains unresolved.
  • No cryo-EM or crystal structure of intact CRL4^CDT2 with substrate and PCNA on DNA
  • Substrate-recognition mechanism for non-PIP-degron targets (CHK1, NIK) unknown
  • How DTL's CDT1-independent G2/M checkpoint function is molecularly mediated remains unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0060090 molecular adaptor activity 3
Localization
GO:0005694 chromosome 3 GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-73894 DNA Repair 6 R-HSA-392499 Metabolism of proteins 4 R-HSA-69306 DNA Replication 3 R-HSA-168256 Immune System 1 R-HSA-9909396 Circadian clock 1
Partners
AURKBCDT1CUL4ADDB1DDB2FBXO11PCNARUVBL1
Complex memberships
CRL4^CDT2 (CUL4–DDB1–CDT2–ROC1)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 DTL (CDT2/L2DTL) is a substrate receptor (DCAF) of the CUL4-DDB1 E3 ubiquitin ligase complex; it contains WD40 repeats and requires a conserved 'WDXR' motif for interaction with DDB1. DTL recruits CDT1 and PCNA to the complex, and is required for S-phase and DNA-damage-induced ubiquitylation and destruction of CDT1, preventing rereplication. Affinity chromatography / mass spectrometry, co-immunoprecipitation, Xenopus egg extract depletion-reconstitution, siRNA knockdown with rereplication readout Molecular cell High 16861906 16949367
2006 DTL/CDT2 is required for the early radiation-induced G2/M checkpoint in a CDT1-independent manner, in addition to its role in preventing rereplication via CDT1 degradation. Genetic epistasis in zebrafish showed that reducing Cdt1 suppresses the rereplication phenotype but not the G2/M checkpoint defect of dtl/cdt2 mutants. Zebrafish forward genetic screen, siRNA knockdown in human cells, genetic epistasis (cdt1 reduction in dtl mutant background) Genes & development High 17085480
2006 L2DTL/CDT2 and PCNA physically interact with p53 and MDM2/HDM2; the CUL4A-L2DTL-PCNA-DDB1-ROC1 complex displays ubiquitin E3 ligase activity toward p53 and this activity depends on MDM2. Inactivation of L2DTL causes p53 stabilization and growth arrest. Anti-CUL4 and anti-L2DTL immunoaffinity chromatography, in vitro ubiquitination assay, siRNA knockdown Cell cycle (Georgetown, Tex.) Medium 16861890
2006 L2dtl (mouse ortholog of DTL) is essential for early embryonic development; its depletion causes mitotic catastrophe, chromosomal lagging, and multinucleation, and reduces PCNA and securin/PTTG1 levels. L2dtl-null embryos arrest at the 4–8-cell stage. Targeted gene knockout in mice, siRNA microinjection into mouse embryos, immunofluorescence and Western blot in HeLa cells The Journal of biological chemistry High 17107960
2006 In S. pombe, Cdt2 is an unstudied WD40-repeat subunit that incorporates into the Pcu4-Ddb1-CSN ubiquitin ligase to target Spd1 (ribonucleotide reductase inhibitor) for degradation during S phase and after DNA damage. Cdt2 co-precipitates with Spd1 and its overexpression causes constitutive Spd1 degradation. Genetic deletion, co-immunoprecipitation, overexpression, cell fractionation in S. pombe The EMBO journal High 16252005 17039252
2010 CRL4(CDT2) monoubiquitinates PCNA at Lys164 in proliferating cells in the absence of exogenous DNA damage, independent of Rad18; this modification is constitutively antagonized by USP1 and is required for translesion DNA synthesis (TLS). In vitro reconstitution confirmed direct PCNA monoubiquitination by CRL4(CDT2). In vitro ubiquitination assay with purified CRL4(CDT2), siRNA knockdown, site-directed mutagenesis (K164R PCNA) Molecular cell High 20129063
2010 CRL4(CDT2) targets the histone methyltransferase Set8/PR-Set7 for ubiquitin-dependent proteolysis during S phase and after DNA damage. Set8 ubiquitylation occurs on chromatin and requires a PIP degron in Set8 that binds PCNA. Aberrant Set8 stabilization causes premature chromatin compaction and H4K20me1 accumulation, triggering G2 arrest. siRNA depletion, expression of PIP-degron mutant Set8, chromatin fractionation, co-immunoprecipitation, cell cycle analysis Molecular cell High 20932472 21035370 21220508
2011 The mechanism of CRL4(CDT2) substrate recognition requires substrates to present a 'PIP degron' on chromatin-loaded PCNA: the degron contains TD residues within the PIP box plus basic amino acids at +3 and +4 downstream, creating a positively charged surface for PCNA contact. Introduction of all required elements into a non-substrate (ligase I peptide) confers degradation. Chimeric Cdt1/ligase I constructs, site-directed mutagenesis, in vivo degradation assays in HeLa cells, electrostatic surface modeling Genes to cells High 21143559 21828267
2011 In Drosophila endocycles, S-phase activation of CRL4(CDT2) drives destruction of the E2F1 transcription factor, creating a window of low CDK activity required for pre-RC assembly and periodic re-replication. Overexpressed E2F1 accelerates endocycling; a stabilized E2F1 blocks endocycling by deregulating CycE and mitotic factors. Drosophila genetics (loss-of-function, gain-of-function), computational modelling, epistasis tests Nature High 22037307
2011 CDT2 is autoubiquitylated by CRL4A and is additionally polyubiquitylated and degraded by CRL1(FBXO11). CRL1(FBXO11)-mediated degradation of CDT2 stabilizes p21 and Set8, regulates TGF-β response, and stimulates epithelial cell migration, partly through Set8 induction that turns off Smad2 activation. Co-immunoprecipitation, siRNA knockdown, in vivo ubiquitination assay, migration assays, TGF-β signaling readouts Molecular cell High 23478441 23478445
2012 CDT2 targets the activated form of CHK1 for CRL4(CDT2)-dependent ubiquitination and destruction in the nucleoplasm rather than on chromatin, and this occurs in a PCNA-independent manner. CHK1 activity is required to maintain G2 arrest in CDT2-depleted cells. siRNA knockdown, co-immunoprecipitation, in vivo ubiquitination assay, subcellular fractionation, cell cycle analysis Molecular and cellular biology Medium 23109433
2013 The F-box protein FBXO11 interacts with CDT2 and recruits it to the SCF(FBXO11) complex for proteasomal degradation. CDK-mediated phosphorylation of Thr464 in CDT2 inhibits (rather than promotes) its recognition by FBXO11, inversely to most SCF substrates. This regulatory interaction is conserved from C. elegans to humans. Affinity purification–mass spectrometry, co-immunoprecipitation, phosphorylation site mutagenesis, proteasome inhibitor experiments Molecular cell High 23478441 23478445
2013 CRL4(CDT2) targets the DNA helicase FBH1 for PCNA-dependent proteolysis via a PIP-degron mechanism after DNA damage; FBH1 degradation is required for the subsequent recruitment of TLS polymerase eta to UV-damaged chromatin, coordinating the HR-to-TLS pathway switch. siRNA knockdown, co-immunoprecipitation, immunofluorescence, expression of non-degradable FBH1 mutant, TLS polymerase eta recruitment assay Nucleic acids research Medium 23677613
2014 14-3-3 adaptor proteins bind CDT2 phosphorylated at Thr464 and shield it from polyubiquitination and proteasomal degradation by SCF(FBXO11). Depletion of 14-3-3 proteins promotes FBXO11–CDT2 interaction. Depletion of 14-3-3γ causes G2/M delay and accumulation of Set8 methyltransferase (a CRL4(CDT2) substrate). Co-immunoprecipitation, phospho-mimicking and alanine mutagenesis, in vivo ubiquitination assay, siRNA knockdown Molecular and cellular biology Medium 25154416
2015 After nucleotide excision repair (NER), XPG endonuclease is targeted for CRL4(CDT2)-dependent proteasomal degradation in a PCNA-dependent manner. Cdt2 is recruited to UV-damage sites and interacts with XPG only in the presence of PCNA; XPG degradation is required for subsequent recruitment of DNA polymerase δ and gap-filling DNA synthesis. In situ Proximity Ligation assay, micropore UV irradiation, siRNA knockdown, co-immunoprecipitation, in vivo ubiquitination assay Cell cycle (Georgetown, Tex.) Medium 25483071
2015 CUL4-DDB1-CDT2 E3 ligase ubiquitinates CRY1 and promotes its degradation; the ligase targets Lys585 within the C-terminal region of CRY1. Depletion of Ddb1, Cdt2, or Pcna stabilizes CRY1 in cells and mouse liver. Overexpression of a non-degradable CRY1-K585A mutant enhances circadian amplitude without altering period length. In vitro ubiquitination assay, siRNA knockdown, in vivo mutagenesis (K585A), bioluminescence reporter for circadian amplitude PloS one Medium 26431207
2018 CRL4(DCAF2/CDT2) in dendritic cells promotes polyubiquitination and degradation of NIK independently of TRAF3 degradation. DCAF2 deficiency causes NIK accumulation, RelB nuclear translocation, and enhanced IL-23 production, exacerbating psoriasis models. DC-conditional Dcaf2 KO mice show increased autoimmune sensitivity. Conditional knockout mice, in vivo ubiquitination assay, transcriptomics, nuclear fractionation, DC co-culture assays The Journal of experimental medicine High 30018073
2018 The C-terminal PIP box of Cdt2 (Cdt2PIP) binds PCNA directly with ~100-fold higher affinity than the Cdt1 PIP box. X-ray crystal structures show Cdt2PIP and Cdt1PIP peptides occupying all three binding sites of the trimeric PCNA ring. Mutating Cdt2PIP weakens PCNA interaction and impairs Cdt1 ubiquitination and degradation in vivo. X-ray crystallography of PCNA–Cdt2PIP and PCNA–Cdt1PIP complexes, isothermal titration calorimetry, mutagenesis, in vivo degradation assays Life science alliance High 30623174
2017 Maternal DCAF2/DTL protein in mouse oocytes is required to prevent DNA re-replication in the first zygotic cell cycle. Oocyte-specific Dcaf2 deletion does not affect oocyte maturation but causes embryonic arrest at the 1–2-cell stage due to prolonged DNA replication and massive DNA damage accumulation. Conditional (oocyte-specific) Dcaf2 knockout mice, BrdU incorporation, γH2AX immunostaining, cell cycle analysis Journal of cell science High 28818995
2019 DTL/CDT2 ubiquitinates PDCD4 (programmed cell death 4), a tumor suppressor, targeting it for proteasomal degradation. Co-IP and immunofluorescence confirmed DTL–PDCD4 interaction; in vitro ubiquitination confirmed DTL-dependent ubiquitination of PDCD4. DTL overexpression accelerates PDCD4 degradation and promotes cancer cell proliferation and migration, which is partially reversed by PDCD4 silencing. Affinity-purification mass spectrometry, co-immunoprecipitation, in vitro ubiquitination assay, siRNA rescue experiments, migration/invasion assays Journal of experimental & clinical cancer research Medium 31409387
2021 The CUL4A-DTL ubiquitin ligase complex targets DNA-PKcs (the catalytic subunit of DNA-PK) in the NHEJ repair pathway for nuclear degradation. Overexpression of CUL4A or DTL reduces NHEJ repair efficiency, increases DSB accumulation, and promotes genomic instability and malignant transformation of normal cells. Co-immunoprecipitation, in vivo ubiquitination assay, NHEJ reporter assay, comet assay, γH2AX quantification, oncogenic transformation assays Oncogene Medium 33627782
2021 DTL overexpression in cervical adenocarcinoma activates JNK through RAC1 and upregulates FOXO1, inducing epithelial-mesenchymal transition, and promoting cell migration and invasion in vitro and intra-pulmonary metastasis in vivo. RNA sequencing after DTL overexpression, siRNA knockdown, in vitro migration/invasion assays, in vivo lung metastasis model, pathway inhibitor studies Cell death & disease Medium 34635635
2021 DDB2 (via CRL4(DDB2)) acts as a novel E3 ubiquitin ligase for CDT2/DTL, promoting its ubiquitination and proteasomal degradation in a PCNA-independent manner. DDB2-mediated CDT2 degradation indirectly regulates CDT1 stability and pre-replication complex assembly (MCM loading). Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, PIP-box mutagenesis, cell synchronization, immunofluorescence Cell & bioscience Medium 33557942
2024 DTL promotes ubiquitination of RUVBL1 (pontin/TIP49), facilitating its binding to RUVBL2 and β-catenin while attenuating its binding to TIP60 acetyltransferase. Ubiquitinated RUVBL1 drives RUVBL1/2-β-catenin-mediated transcriptional upregulation of NHEJ repair genes, reduces TIP60-dependent H4K16 acetylation and HR repair, and enhances radiation resistance in breast cancer cells. Co-immunoprecipitation, in vivo ubiquitination assay, chromatin immunoprecipitation, siRNA knockdown, in vivo tumor irradiation model Cell death & disease Medium 38609375
2008 DTL/RAMP protein shows cell-cycle-dependent localization: nuclear in interphase and concentrated at the contractile ring during cytokinesis. Expression peaks at G1/S phase, and phosphorylation increases during mitosis. DTL interacts with Aurora kinase B (AURKB) in vitro, and AURKB depletion reduces DTL phosphorylation and destabilizes DTL protein. Immunocytochemistry, Western blot (cell cycle-synchronized cells), in vitro kinase assay with Aurora B, siRNA knockdown Oncogene Medium 18542055
2006 L2DTL/CDT2 protein localizes to the nucleus during interphase and to centrosomes (co-localizing with γ-tubulin and Aurora A) throughout the cell cycle in hepatocellular carcinoma cells. L2DTL protein is degraded in mitosis via the APC/C-Cdh1 complex. Immunostaining, centrosome isolation and co-fractionation with γ-tubulin, Western blot across cell cycle, RNAi knockdown Cell cycle (Georgetown, Tex.) Medium 17106265
2018 CDT2 overexpression activates CDK activity by downregulating p21, inducing tau hyperphosphorylation and Aβ toxicity in a model of Alzheimer's disease. CDK inhibition by roscovitine rescues CDT2-induced cognitive defects in mice, placing CDT2 upstream of CDKs in a pathological cell-cycle re-entry pathway. Lentiviral DTL overexpression in mice, RNA-seq, roscovitine rescue, behavioral testing, Western blot for p21/CDK targets Alzheimer's & dementia Medium 30321504
2011 MNNG-induced alkylation damage triggers rapid p21 degradation through a pathway requiring Cdt2 ubiquitin ligase, PCNA, and MSH2 (but not MLH1). MNNG induces formation of PCNA–MSH6–Cdt2 complexes on chromatin, and blocking p21 degradation impairs MMR protein chromatin recruitment. siRNA knockdown, co-immunoprecipitation, chromatin fractionation, p21 mutants (PCNA-binding deficient), proteasome inhibitor experiments The Journal of biological chemistry Medium 21725088

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Molecular cell 536 16949367
2012 Essential features and rational design of CRISPR RNAs that function with the Cas RAMP module complex to cleave RNAs. Molecular cell 225 22227116
2010 Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage. Molecular cell 202 21035370
2011 Mechanism of CRL4(Cdt2), a PCNA-dependent E3 ubiquitin ligase. Genes & development 193 21828267
2010 CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Molecular cell 188 20932472
2006 L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage. Cell cycle (Georgetown, Tex.) 153 16861906
2012 MiR-30a-5p suppresses tumor growth in colon carcinoma by targeting DTL. Carcinogenesis 149 22287560
2006 DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes & development 140 17085480
2010 CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Molecular cell 138 20129063
2019 A short translational ramp determines the efficiency of protein synthesis. Nature communications 129 31852903
2011 Control of Drosophila endocycles by E2F and CRL4(CDT2). Nature 129 22037307
2018 Quantitative and Qualitative Assessment of the Posterior Medial Meniscus Anatomy: Defining Meniscal Ramp Lesions. The American journal of sports medicine 126 30525875
2006 L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes. Cell cycle (Georgetown, Tex.) 114 16861890
2011 SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation. The Journal of cell biology 101 21220508
2005 Probing the mechanical folding kinetics of TAR RNA by hopping, force-jump, and force-ramp methods. Biophysical journal 93 16214869
2019 DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation. Journal of experimental & clinical cancer research : CR 92 31409387
2011 1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma. Oncogene 88 21822310
2006 Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury. Experimental brain research 84 16718433
2005 Transactivation of Schizosaccharomyces pombe cdt2+ stimulates a Pcu4-Ddb1-CSN ubiquitin ligase. The EMBO journal 83 16252005
2008 Involvement of elevated expression of multiple cell-cycle regulator, DTL/RAMP (denticleless/RA-regulated nuclear matrix associated protein), in the growth of breast cancer cells. Oncogene 81 18542055
2009 High specific infectivity of plasma virus from the pre-ramp-up and ramp-up stages of acute simian immunodeficiency virus infection. Journal of virology 78 19129448
2006 DNA damage induces Cdt1 proteolysis in fission yeast through a pathway dependent on Cdt2 and Ddb1. EMBO reports 78 17039252
2004 Cartilage injury by ramp compression near the gel diffusion rate. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 77 14656673
2013 Ubiquitin E3 ligase CRL4(CDT2/DCAF2) as a potential chemotherapeutic target for ovarian surface epithelial cancer. The Journal of biological chemistry 75 23995842
2012 Targeting a family B GPCR/RAMP receptor complex: CGRP receptor antagonists and migraine. British journal of pharmacology 74 21871019
2006 Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma. Cell cycle (Georgetown, Tex.) 74 17106265
2011 Resolution-associated molecular patterns (RAMP): RAMParts defending immunological homeostasis? Clinical and experimental immunology 72 21671907
2001 Expression of receptor-activity modifying protein (RAMP) mRNAs in the mouse brain. Brain research. Molecular brain research 72 11532336
2013 Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. Molecular cell 70 23478441
1987 Analysis of cerebellar motor disorders by visually-guided elbow tracking movement. 2. Contribution of the visual cues on slow ramp pursuit. Brain : a journal of neurology 70 3801845
2013 CRL1-FBXO11 promotes Cdt2 ubiquitylation and degradation and regulates Pr-Set7/Set8-mediated cellular migration. Molecular cell 69 23478445
2013 The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells. Nucleic acids research 69 23677613
2011 Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development. Trends in pharmacological sciences 66 21722971
2008 Optical monitoring of neuronal activity at high frame rate with a digital random-access multiphoton (RAMP) microscope. Journal of neuroscience methods 66 18634822
2019 Multiplexed analysis of the secretin-like GPCR-RAMP interactome. Science advances 65 31555726
2018 RANGER-DTL 2.0: rigorous reconstruction of gene-family evolution by duplication, transfer and loss. Bioinformatics (Oxford, England) 63 29688310
2016 Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma. EBioMedicine 60 27333051
2012 CRL4(CDT2) targets CHK1 for PCNA-independent destruction. Molecular and cellular biology 58 23109433
2017 Ubiquitin-conjugating enzyme E2T (UBE2T) and denticleless protein homolog (DTL) are linked to poor outcome in breast and lung cancers. Scientific reports 57 29235520
2011 Shared and separate functions of the RAMP-based adrenomedullin receptors. Peptides 57 21645567
1999 Effects of pressure ramp slope values on the work of breathing during pressure support ventilation in restrictive patients. Critical care medicine 47 10321660
2018 RaMP: A Comprehensive Relational Database of Metabolomics Pathways for Pathway Enrichment Analysis of Genes and Metabolites. Metabolites 45 29470400
2015 Overexpression of denticleless E3 ubiquitin protein ligase homolog (DTL) is related to poor outcome in gastric carcinoma. Oncotarget 45 26472028
2014 14-3-3 proteins play a role in the cell cycle by shielding cdt2 from ubiquitin-mediated degradation. Molecular and cellular biology 45 25154416
2013 Role of CGRP-receptor component protein (RCP) in CLR/RAMP function. Current protein & peptide science 40 23745704
2004 Crystallographic structure of the nuclease domain of 3'hExo, a DEDDh family member, bound to rAMP. Journal of molecular biology 40 15451662
2018 CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis. The Journal of experimental medicine 39 30018073
2023 RaMP-DB 2.0: a renovated knowledgebase for deriving biological and chemical insight from metabolites, proteins, and genes. Bioinformatics (Oxford, England) 37 36373969
2005 DTL, the Drosophila homolog of PIMT/Tgs1 nuclear receptor coactivator-interacting protein/RNA methyltransferase, has an essential role in development. The Journal of biological chemistry 37 15684427
2020 CRL4Cdt2: Coupling Genome Stability to Ubiquitination. Trends in cell biology 32 32044173
2014 Evidence of a critical role for cellodextrin transporte 2 (CDT-2) in both cellulose and hemicellulose degradation and utilization in Neurospora crassa. PloS one 32 24586693
2012 The response of Na(V)1.3 sodium channels to ramp stimuli: multiple components and mechanisms. Journal of neurophysiology 32 23114218
2010 Positively charged residues located downstream of PIP box, together with TD amino acids within PIP box, are important for CRL4(Cdt2) -mediated proteolysis. Genes to cells : devoted to molecular & cellular mechanisms 32 21143559
2018 CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 31 30321504
2018 Targeting DTL induces cell cycle arrest and senescence and suppresses cell growth and colony formation through TPX2 inhibition in human hepatocellular carcinoma cells. OncoTargets and therapy 30 29606879
2016 The expanding repertoire of receptor activity modifying protein (RAMP) function. Critical reviews in biochemistry and molecular biology 30 26740457
1999 Desensitization of CGRP and adrenomedullin receptors in SK-N-MC cells: implications for the RAMP hypothesis. Endocrinology 28 9886866
2019 Adult Cardiomyocyte Cell Cycle Detour: Off-ramp to Quiescent Destinations. Trends in endocrinology and metabolism: TEM 27 31262545
2012 RAMP like proteins : RTP and REEP family of proteins. Advances in experimental medicine and biology 26 22434109
1996 Response of cardiac myocytes to a ramp increase of diacylglycerol generated by photolysis of a novel caged diacylglycerol. Biophysical journal 26 9172772
2015 Cdt2-mediated XPG degradation promotes gap-filling DNA synthesis in nucleotide excision repair. Cell cycle (Georgetown, Tex.) 25 25483071
2019 Reversible association with motor proteins (RAMP): A streptavidin-based method to manipulate organelle positioning. PLoS biology 24 31100061
2013 Positive charge loading at protein termini is due to membrane protein topology, not a translational ramp. Molecular biology and evolution 24 24077849
2003 The Schizosaccharomyces pombe cdt2(+) gene, a target of G1-S phase-specific transcription factor complex DSC1, is required for mitotic and premeiotic DNA replication. Genetics 24 12871901
2021 CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation. Oncogene 23 33627782
2021 Overexpression of DTL enhances cell motility and promotes tumor metastasis in cervical adenocarcinoma by inducing RAC1-JNK-FOXO1 axis. Cell death & disease 23 34635635
2015 CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1. PloS one 22 26431207
2006 L2dtl is essential for cell survival and nuclear division in early mouse embryonic development. The Journal of biological chemistry 22 17107960
2019 Development of chimeric and bifunctional antagonists for CLR/RAMP receptors. PloS one 21 31150417
2011 N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) triggers MSH2 and Cdt2 protein-dependent degradation of the cell cycle and mismatch repair (MMR) inhibitor protein p21Waf1/Cip1. The Journal of biological chemistry 21 21725088
2022 Role of DTL in Hepatocellular Carcinoma and Its Impact on the Tumor Microenvironment. Frontiers in immunology 20 35392073
2017 Development of diagnostic SCAR markers for genomic DNA amplifications in breast carcinoma by DNA cloning of high-GC RAMP-PCR fragments. Oncotarget 20 28410206
2016 KSP inhibitor SB743921 inhibits growth and induces apoptosis of breast cancer cells by regulating p53, Bcl-2, and DTL. Anti-cancer drugs 20 27379929
2014 C/EBPα regulates CRL4(Cdt2)-mediated degradation of p21 in response to UVB-induced DNA damage to control the G1/S checkpoint. Cell cycle (Georgetown, Tex.) 20 25483090
2006 Risk assessment of patient handling with ambulance stretcher systems (ramp/(winch), easi-loader, tail-lift) using biomechanical failure criteria. Medical engineering & physics 20 17064948
1988 Threshold for repetitive activity for a slow stimulus ramp: a memory effect and its dependence on fluctuations. Biophysical journal 20 3207840
2022 Single agent VS-6766 or VS-6766 plus defactinib in KRAS-mutant non-small-cell lung cancer: the RAMP-202 phase II trial. Future oncology (London, England) 19 35285277
2018 Regulation of cardiovascular development and homeostasis by the adrenomedullin-RAMP system. Peptides 19 29689347
2017 Maternal DCAF2 is crucial for maintenance of genome stability during the first cell cycle in mice. Journal of cell science 19 28818995
2013 Regulation of adrenomedullin and its family peptide by RAMP system--lessons from genetically engineered mice. Current protein & peptide science 19 23745699
2005 Prestrain decreases cartilage susceptibility to injury by ramp compression in vitro. Osteoarthritis and cartilage 19 16165378
2022 miR-34a negatively regulates cell cycle factor Cdt2/DTL in HPV infected cervical cancer cells. BMC cancer 18 35840896
2022 Optimizing component formula suppresses lung cancer by blocking DTL-mediated PDCD4 ubiquitination to regulate the MAPK/JNK pathway. Journal of ethnopharmacology 18 35850313
2013 Regulation of TGF-β signaling, exit from the cell cycle, and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2. Cell cycle (Georgetown, Tex.) 18 23892434
2012 The mysterious RAMP proteins and their roles in small RNA-based immunity. Protein science : a publication of the Protein Society 18 22323284
2025 Efficacy and Safety of Avutometinib ± Defactinib in Recurrent Low-Grade Serous Ovarian Cancer: Primary Analysis of ENGOT-OV60/GOG-3052/RAMP 201. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 17 40644648
2014 The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase. Oncotarget 17 25115388
2020 Small and large cutaneous fibers display different excitability properties to slowly increasing ramp pulses. Journal of neurophysiology 16 32783585
2019 Membrane-Protein Unfolding Intermediates Detected with Enhanced Precision Using a Zigzag Force Ramp. Biophysical journal 16 31882249
2018 Evolution of Diabetes Care in Hong Kong: From the Hong Kong Diabetes Register to JADE-PEARL Program to RAMP and PEP Program. Endocrinology and metabolism (Seoul, Korea) 16 29589385
2018 Direct binding of Cdt2 to PCNA is important for targeting the CRL4Cdt2 E3 ligase activity to Cdt1. Life science alliance 16 30623174
2002 Functional interaction of G protein-coupled receptors of the adrenomedullin peptide family with accessory receptor-activity-modifying proteins (RAMP). Microscopy research and technique 16 11921352
2024 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 15 38609375
2021 DDB2 regulates DNA replication through PCNA-independent degradation of CDT2. Cell & bioscience 15 33557942
2016 How to Properly Measure a Current-Voltage Relation?-Interpolation vs. Ramp Methods Applied to Studies of GABAA Receptors. Frontiers in cellular neuroscience 15 26869882
2008 Transcriptional regulation of an evolutionary conserved intergenic region of CDT2-INTS7. PloS one 15 18213392
2023 In Vitro Evolution to Increase the Titers of Difficult Bacteriophages: RAMP-UP Protocol. PHAGE (New Rochelle, N.Y.) 14 37350994
2016 Evaluation of genetic diversity of Clinacanthus nutans (Acanthaceaea) using RAPD, ISSR and RAMP markers. Physiology and molecular biology of plants : an international journal of functional plant biology 14 27924125
2009 Recruitment maneuver: RAMP versus CPAP pressure profile in a model of acute lung injury. Respiratory physiology & neurobiology 14 19712760
2000 Na+-Ca2+ exchange current from rabbit isolated atrioventricular nodal and ventricular myocytes compared using action potential and ramp waveforms. Acta physiologica Scandinavica 14 10712577