Affinage

Showing DTL — CDT2 is a alias.

DTL

Denticleless protein homolog · UniProt Q9NZJ0

Length
730 aa
Mass
79.5 kDa
Annotated
2026-06-09
95 papers in source corpus 43 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DTL (CDT2/DCAF2/L2DTL) is the substrate-recognition subunit (DCAF) of the CUL4-DDB1 (CRL4) E3 ubiquitin ligase, which it converts into a PCNA-coupled proteolytic machine that links protein destruction to DNA synthesis (PMID:16949367, PMID:16861906). CDT2 docks onto DNA-loaded PCNA through a C-terminal PIP box that binds PCNA with roughly two orders of magnitude higher affinity than canonical PIP boxes and occupies all three sites of the trimeric ring (PMID:30623174, PMID:30301766), and an adjacent C-terminal DNA-binding region further potentiates ligase activity (PMID:30649446); substrates are recognized through a specialized 'PIP degron' that requires TD residues within the PIP box plus a basic residue at the +3/+4 position (PMID:21143559). Through this mechanism CRL4(CDT2) ubiquitylates substrates on chromatin during S phase and after DNA damage to safeguard genome integrity: it destroys the licensing factor CDT1 to prevent rereplication (PMID:16949367, PMID:16861906, PMID:17085480), degrades the histone methyltransferase SET8/PR-Set7 to control H4K20me1 and chromatin compaction (PMID:20932472, PMID:21220508, PMID:21035370), and removes p21, the DNA polymerase delta p12 subunit, FBH1, XPG, and TDG to coordinate replication, translesion synthesis, and nucleotide excision repair, while also monoubiquitylating PCNA itself to promote TLS (PMID:20129063, PMID:21725088, PMID:23677613, PMID:23913683, PMID:25483071, PMID:38837535). CRL4(CDT2) extends beyond replication to checkpoint control, degrading activated CHK1 in the nucleoplasm (PMID:23109433), and to the circadian clock, where it targets CRY1 to set Bmal1 oscillation amplitude (PMID:26431207). CDT2 activity is itself tightly regulated: CDK phosphorylation of its C-terminus lowers PCNA affinity and inactivates the ligase (PMID:29424068), ATR phosphorylation after UV accelerates substrate degradation (PMID:23029527), and its abundance is controlled by multiple ligases and adaptors including SCF(FBXO11) opposed by 14-3-3 shielding of phospho-Thr464 (PMID:23478441, PMID:23478445, PMID:25154416), DDB2 (PMID:33557942), TRIM22 (PMID:40680432), and APC/C-Cdh1 in mitosis (PMID:17106265). Genetic ablation establishes CDT2 as essential for genome stability in the early embryonic, oocyte, and spermatogonial cell cycles (PMID:17107960, PMID:28818995, PMID:38837535), and the protein is co-opted in cancer, where it degrades tumor suppressors such as PDCD4, SMAD4, SLTM, and ARGLU1 to drive proliferation, Notch and Wnt signaling, and therapy resistance (PMID:31409387, PMID:41203163, PMID:39384740, PMID:38218284). Cryo-EM structures of the DCAF2:DDB1:DDA1 complex define how a covalent ligand engaging WD40 residue C141 enables PROTAC-mediated neosubstrate recruitment (PMID:41045927).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2006 High

    Established the founding identity of DTL/CDT2 as a substrate receptor for the CUL4-DDB1 ligase that couples CDT1 destruction to ongoing DNA synthesis, explaining how cells avoid rereplication.

    Evidence DCAF identification by affinity-MS, Xenopus extract reconstitution, and siRNA knockdown in human cells with rereplication phenotype

    PMID:16861906 PMID:16949367 PMID:17085480

    Open questions at the time
    • Did not resolve the structural basis of PCNA engagement
    • Mechanism of damage-induced versus S-phase recruitment not separated
  2. 2006 High

    Demonstrated CDT2 is genetically essential, with knockout causing early embryonic lethality and depletion causing mitotic catastrophe, showing the ligase is required for viable cell-cycle progression.

    Evidence Targeted gene disruption in mice, siRNA microinjection into embryos, and RNAi in HeLa cells

    PMID:17107960

    Open questions at the time
    • Substrate(s) responsible for lethality not pinpointed in vivo
    • Did not distinguish replication-licensing from checkpoint contributions
  3. 2006 Medium

    Linked CDT2 to p53 pathway regulation by implicating CUL4A-CDT2-PCNA in MDM2 and p53 turnover, broadening its role beyond replication licensing.

    Evidence Co-IP and in vitro ubiquitination with siRNA knockdown

    PMID:16861890

    Open questions at the time
    • Direct versus indirect effects on p53 not fully separated
    • Single lab
  4. 2008 Medium

    Characterized cell-cycle-dependent localization and identified Aurora kinase B phosphorylation controlling CDT2 stability, indicating mitotic regulation of the protein.

    Evidence Immunocytochemistry, in vitro AURKB kinase assay, and AURKB knockdown

    PMID:17106265 PMID:18542055

    Open questions at the time
    • Functional consequence of contractile-ring/centrosome localization unresolved
    • Phosphosite mapping incomplete
  5. 2010 High

    Defined the molecular grammar of CRL4(CDT2) targeting—the PIP degron with TD residues and downstream basic residue—and showed it can convert a non-substrate into a substrate, providing a predictive substrate code.

    Evidence Chimera and mutagenesis of CDT1/Ligase I with cellular degradation assays

    PMID:21143559

    Open questions at the time
    • Structural basis of degron-PCNA-CDT2 recognition not yet visualized
    • Did not address why some PIP proteins escape degradation
  6. 2010 High

    Expanded the substrate repertoire into chromatin and replication regulation by establishing PCNA-coupled degradation of SET8/PR-Set7 (controlling H4K20me1) and monoubiquitination of PCNA promoting translesion synthesis.

    Evidence PIP-degron mutagenesis, laser micro-irradiation, ChIP, in vitro ubiquitination, and TLS assays

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

    Open questions at the time
    • Relative S-phase versus damage contributions of each substrate not fully partitioned
    • PCNA monoubiquitination versus Rad18 pathway interplay incompletely defined
  7. 2011 Medium

    Showed CRL4(CDT2) function reaches checkpoint and transcriptional control by degrading activated CHK1 (in the nucleoplasm, PCNA-independent) and oscillatory destruction of E2F1, revealing context-dependent recruitment modes.

    Evidence Co-IP, compartment fractionation, knockdown in human cells, and Drosophila genetic epistasis with computational modeling

    PMID:22037307 PMID:23109433

    Open questions at the time
    • PCNA-independent recruitment mechanism for CHK1 unresolved
    • E2F1 oscillator demonstrated in Drosophila endocycles, not human mitotic cycles
  8. 2011 Medium

    Connected CDT2 to mismatch repair and replication fidelity by linking alkylation-induced p21 degradation and Pol delta p12 turnover to chromatin repair-factor recruitment.

    Evidence PCNA-binding mutant analysis, chromatin fractionation, PIP-degron mutagenesis, and knockdown

    PMID:21725088 PMID:23913683

    Open questions at the time
    • Direct ubiquitination of these substrates by CRL4(CDT2) inferred from cellular assays
    • Single lab for each substrate
  9. 2013 High

    Revealed how CDT2 abundance is itself controlled, with SCF(FBXO11) degrading CDT2 antagonistically to CDK phosphorylation at Thr464, defining cross-ligase regulation that times cell-cycle exit and TGF-beta responses.

    Evidence Affinity-MS, phospho-degron mutagenesis, in vitro ubiquitination, C. elegans epistasis, and signaling/migration assays

    PMID:23478441 PMID:23478445

    Open questions at the time
    • Quantitative balance of autoubiquitylation versus FBXO11 in vivo not resolved
    • Tissue-specific relevance of CDT2 turnover unaddressed
  10. 2013 Medium

    Extended the DNA-damage substrate set to FBH1, showing degradation of this anti-recombinase helicase facilitates TLS polymerase eta recruitment after UV.

    Evidence Non-degradable FBH1 mutant, Co-IP, chromatin fractionation, and immunofluorescence

    PMID:23677613

    Open questions at the time
    • Single lab
    • In vivo genome-stability consequence of FBH1 stabilization not measured
  11. 2014 Medium

    Identified 14-3-3 proteins as phospho-Thr464-dependent shields that protect CDT2 from FBXO11, adding a layer of stability control required for cell-cycle progression.

    Evidence Phospho-mimicking/blocking CDT2 mutants, Co-IP, ubiquitination assays, and cell-cycle analysis

    PMID:25154416

    Open questions at the time
    • Which signals drive 14-3-3 binding dynamics not defined
    • Single lab
  12. 2015 High

    Broadened CRL4(CDT2) function into nucleotide excision repair completion and the circadian clock by degrading XPG after lesion incision and targeting CRY1 at Lys585 to set Bmal1 oscillation amplitude.

    Evidence Proximity ligation, NER synthesis assays, in vitro ubiquitination with K585A mutant, mouse liver, and luciferase circadian reporters

    PMID:25483071 PMID:26431207

    Open questions at the time
    • PCNA dependence of CRY1 targeting in vivo not fully resolved
    • Tissue specificity of circadian role beyond liver untested
  13. 2018 High

    Provided the structural and biochemical basis for CDT2 substrate-targeting via its uniquely high-affinity C-terminal PIP box that occupies all three PCNA sites, and showed CDK phosphorylation inactivates the ligase by lowering PCNA affinity.

    Evidence X-ray crystallography of PCNA-PIP peptide complexes, binding assays, Cdt2PIP and 18-site CDK mutagenesis, and in vitro/cellular ubiquitination assays

    PMID:29424068 PMID:30301766 PMID:30623174

    Open questions at the time
    • Full CRL4(CDT2)-substrate-PCNA-DNA assembly not visualized
    • How DNA loading is sensed structurally remains open
  14. 2018 High

    Established immune and developmental roles by showing DCAF2 degrades NIK in dendritic cells and controls M-phase exit in T cells via H4K20me1, linking the ligase to autoimmunity and lymphocyte proliferation.

    Evidence Conditional knockout mice, in vivo ubiquitination, H4K20me1 ChIP, proteasome activity, and immunological assays

    PMID:30018073 PMID:30245026

    Open questions at the time
    • Whether NIK targeting is PCNA-coupled not addressed
    • M-phase H4K20me1-Aurkb axis mechanistic chain partly correlative
  15. 2019 Medium

    Defined a C-terminal DNA-binding domain that enhances ligase activity and showed the WD40 region alone supports complex formation but not full activity, refining the domain architecture of catalysis.

    Evidence Domain deletion, DNA-binding and in vitro ubiquitination assays, cellular CDT1 degradation

    PMID:30649446

    Open questions at the time
    • Structural integration of DNA-binding domain with PIP box and PCNA unknown
    • Single lab
  16. 2021 Medium

    Expanded oncogenic substrate signaling—degrading DNA-PKcs to impair NHEJ and ubiquitinating RUVBL1 to reroute chromatin and transcriptional programs—linking CDT2 dysregulation to genomic instability and radioresistance.

    Evidence Co-IP, ubiquitination and NHEJ repair assays, xenografts, and immunohistochemistry

    PMID:33627782 PMID:38609375

    Open questions at the time
    • PCNA/degron dependence of these substrates not established
    • Single lab per substrate
  17. 2021 Medium

    Added DDB2 as an additional regulator that degrades CDT2 PCNA-independently, indirectly tuning CDT1 stability and pre-replication complex assembly.

    Evidence In vivo ubiquitination, PIP-box mutagenesis, knockdown/overexpression, and FACS

    PMID:33557942

    Open questions at the time
    • Physiological context where DDB2 dominates CDT2 turnover unclear
    • Single lab
  18. 2023 Medium

    Showed CDT2 activity must be restrained at stalled replication forks, with DCAF14 limiting CDT2-driven SET8 loss to prevent nuclease-mediated nascent DNA degradation and fork collapse.

    Evidence siRNA knockdown, fork protection assays, and SET8 rescue experiments

    PMID:37940188

    Open questions at the time
    • Mechanism by which DCAF14 modulates CDT2 not defined
    • Single lab
  19. 2024 High

    Demonstrated germline-specific requirements for CDT2 in maintaining spermatogonial proliferation and meiotic entry through degradation of p21 and TDG, paralleling its essential maternal role.

    Evidence Germ cell-specific conditional knockout mice with substrate rescue and apoptosis assays

    PMID:28818995 PMID:38837535

    Open questions at the time
    • Relative contribution of p21 versus TDG in vivo not fully partitioned
    • Whether other substrates contribute to phenotype untested
  20. 2024 Medium

    Established DTL as an oncogenic driver in solid tumors through novel-linkage ubiquitination of SMAD4 (K48), SLTM, and ARGLU1 (K11) to activate Wnt and Notch signaling, broadening its substrate landscape into developmental signaling.

    Evidence MS, Co-IP, linkage-specific ubiquitination assays, ChIP, rescue, and in vivo tumor models

    PMID:38218284 PMID:39384740 PMID:41203163

    Open questions at the time
    • PCNA/degron requirements for these substrates not tested
    • Single lab per substrate
  21. 2025 High

    Provided cryo-EM structures of the DCAF2:DDB1:DDA1 complex and a PROTAC ternary complex with BRD4, identifying WD40 residue C141 as a covalent handle for targeted protein degradation, establishing CDT2 as a druggable ligase scaffold.

    Evidence Cryo-EM structure determination, in vitro ubiquitination, and cellular TPD assays with covalent compounds

    PMID:41045927

    Open questions at the time
    • Structure of an endogenous-substrate ternary complex not solved
    • Selectivity of C141-targeting ligands in cells incompletely characterized
  22. 2025 Medium

    Identified additional upstream ligases—TRIM22 (downregulated by HPV E6) and Mdm2—that control CDT2 abundance, linking CDT2 dysregulation to viral oncogenesis and senescence via SET8/p21 stabilization.

    Evidence Co-IP, ubiquitination assays, ChIP, knockdown/overexpression, and senescence assays (one preprint)

    PMID:40680432 PMID:bio_10.1101_2025.07.09.663887

    Open questions at the time
    • Mdm2 finding is a non-peer-reviewed preprint awaiting validation
    • Hierarchy among the multiple CDT2-degrading ligases in different contexts unresolved
  23. 2025 Medium

    Extended CDT2 substrate biology to ferroptosis and tissue injury through PROX1 degradation in hepatocytes during ischemia/reperfusion, with sex-dependent expression governing injury severity.

    Evidence Multi-omics, Co-IP, ubiquitination assays, and in vivo I/R mouse models with ferroptosis markers

    PMID:40560731

    Open questions at the time
    • Whether PROX1 degradation is PCNA-coupled unaddressed
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the full CRL4(CDT2) holoenzyme engages a PIP-degron substrate on DNA-loaded PCNA at atomic resolution, and how the many competing CDT2-degrading ligases are coordinated to set ligase activity in distinct tissues and disease states.
  • No structure of an endogenous substrate-PCNA-CRL4(CDT2) ternary complex
  • Quantitative integration of FBXO11, DDB2, TRIM22, Mdm2, and APC/C control of CDT2 levels lacking
  • Substrate-selectivity rules across tissues not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0060090 molecular adaptor activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-69306 DNA Replication 4 R-HSA-73894 DNA Repair 4 R-HSA-4839726 Chromatin organization 3 R-HSA-168256 Immune System 2 R-HSA-9909396 Circadian clock 1
Partners
CDT1CUL4ADDA1DDB1DDB2FBXO11PCNA
Complex memberships
CRL4(CDT2) / CUL4-DDB1-CDT2 E3 ubiquitin ligase

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 DTL/CDT2/DCAF2 is a substrate receptor (DCAF) for the CUL4-DDB1 E3 ubiquitin ligase complex. It is recruited to replication forks via CDT1 and PCNA, where it ubiquitylates CDT1 to promote its destruction in S phase and after DNA damage, preventing rereplication. Depletion of human CDT2 causes rereplication and checkpoint activation. Affinity purification/mass spectrometry identification of DCAFs; Xenopus egg extract depletion/reconstitution assays; siRNA knockdown in human cells; Co-IP; cell cycle analysis Molecular cell High 16949367
2006 L2DTL/CDT2 associates with CUL4, DDB1, and PCNA in human cells, and loss of L2DTL suppresses CDT1 proteolysis in response to DNA damage. PCNA interacts with CDT1 and is required for CDT1 proteolysis after DNA damage. Inactivation of L2DTL causes dissociation of DDB1 from the CUL4 complex. Anti-CUL4 antibody affinity chromatography/mass spectrometry; anti-L2DTL immunoaffinity chromatography; Co-IP; siRNA knockdown in Drosophila S2 and human cells; Western blot Cell cycle (Georgetown, Tex.) High 16861906
2006 L2DTL/CDT2 and PCNA physically interact with p53 and MDM2/HDM2. CUL4A complexes display polyubiquitination activity towards p53 dependent on L2DTL, PCNA, DDB1, ROC1, and MDM2. Inactivation of CUL4A, L2DTL, PCNA, DDB1, or ROC1 induces p53 stabilization and growth arrest. MDM2 is rapidly proteolyzed after UV irradiation through a CUL4/DDB1- and PCNA-regulated mechanism. Co-IP; in vitro ubiquitination assay; siRNA knockdown; Western blot Cell cycle (Georgetown, Tex.) Medium 16861890
2006 DTL/CDT2 is an essential component of the CUL4-DDB1 E3 ubiquitin ligase that controls CDT1 levels, preventing rereplication. DTL is also required for the early radiation-induced G2/M checkpoint independently of CDT1. In zebrafish, reduction of Cdt1 suppresses the rereplication defect of dtl/cdt2-deficient fish but not the G2/M checkpoint defect, establishing two distinct mechanistic roles. Zebrafish forward genetic screen; genetic epistasis (cdt1 reduction in dtl mutants); human DTL siRNA knockdown; cell cycle analysis Genes & development High 17085480
2006 L2dtl gene knockout in mice results in early embryonic lethality at the 4-8 cell stage. siRNA-mediated depletion of L2dtl in mouse embryos causes cell cycle progression failure, mitotic catastrophe (chromosomal fragmentation and lagging), and failure to develop to blastocysts. In HeLa cells, L2dtl depletion results in multinucleation and downregulation of PCNA and PTTG1/securin. Targeted gene disruption in mice; microinjection of siRNA into two-cell embryos; RNAi in HeLa cells; morphological analysis; Western blot The Journal of biological chemistry High 17107960
2006 L2DTL protein localizes to the nucleus during interphase and concentrates at centrosomes (co-localizing with gamma-tubulin and Aurora-A) throughout the cell cycle. L2DTL protein is degraded in mitosis by the APC/C-Cdh1 complex. L2DTL gene expression peaks at G1/S phase. Immunostaining; Western blotting; centrosome isolation/co-fractionation with gamma-tubulin; cell cycle synchronization Cell cycle (Georgetown, Tex.) Medium 17106265
2008 DTL/RAMP protein shows cell-cycle-dependent localization in breast cancer cells: nuclear during interphase and concentrated at the contractile ring during cytokinesis. DTL/RAMP is phosphorylated by Aurora kinase B (AURKB) in vitro. Depletion of AURKB reduces DTL/RAMP phosphorylation and decreases DTL/RAMP protein stability. Immunocytochemistry; Western blot; in vitro kinase assay with AURKB; siRNA knockdown of AURKB; cell cycle analysis Oncogene Medium 18542055
2010 CRL4(CDT2) ubiquitylates and destroys the histone methyltransferase Set8/PR-Set7 during S phase and after DNA damage. Set8 ubiquitylation occurs on chromatin and requires a specific PIP degron in Set8 that binds PCNA. Inactivation of CRL4(CDT2) leads to Set8 stabilization, aberrant H4K20me1 accumulation, premature chromatin compaction, and checkpoint-mediated G2 arrest. siRNA knockdown; overexpression of Set8 PIP-degron mutant; cell cycle analysis; H4K20me1 chromatin immunoprecipitation; Western blot Molecular cell High 20932472 21220508
2010 CRL4(CDT2) E3 ubiquitin ligase monoubiquitinates PCNA at Lys164 independently of Rad18 in proliferating cells. This is antagonized by USP1. CRL4(CDT2)-mediated PCNA monoubiquitination promotes translesion DNA synthesis (TLS) in nondamaged cells. In vitro ubiquitination assay; siRNA knockdown of CRL4(CDT2) components; PCNA Lys164 mutagenesis; TLS assay Molecular cell High 20129063
2010 PR-Set7 is degraded during S phase and after DNA damage via PCNA-coupled CRL4(CDT2)-dependent proteolysis. PR-Set7 interaction with PCNA through a specialized 'PIP degron' domain targets it for this degradation. PR-Set7 is transiently recruited to laser-induced DNA damage sites through its interaction with PCNA, and 53BP1 recruitment to damage sites depends on PR-Set7 catalytic activity. Western blot; PIP degron mutagenesis; laser micro-irradiation live imaging; siRNA knockdown; cell cycle analysis Molecular cell High 21035370
2011 In Drosophila endocycles, S-phase activates the CRL4(CDT2) ubiquitin ligase, which mediates destruction of E2F1 transcription factor. This creates a molecular oscillator: E2F1 promotes CycE expression and S-phase initiation, S-phase activates CRL4(CDT2), which destroys E2F1, allowing low CDK activity needed for pre-RC formation for the next S-phase. Genetic epistasis in Drosophila; computational modeling; overexpression/stabilized E2F1 mutant analysis; genetic tests Nature High 22037307
2011 CRL4(CDT2) targets CHK1 for ubiquitin-mediated destruction in the nucleoplasm (not on chromatin) in a PCNA-independent manner, targeting the activated form of CHK1. CDT2-depleted cells show G2 arrest, and CHK1 activity is required for maintaining this G2 arrest. CRL1 and CRL4 both ubiquitinate CHK1 but bind CHK1 in distinct cellular compartments. Co-IP; siRNA knockdown; Western blot; cell cycle analysis; compartment fractionation Molecular and cellular biology Medium 23109433
2011 MNNG-induced DNA alkylation triggers rapid p21 degradation via the ubiquitin ligase CDT2 and the proteasome. This degradation requires MSH2 but not MLH1, and requires p21's ability to bind PCNA. MNNG induces formation of PCNA complexes with MSH6 and CDT2. When p21 degradation is blocked, MMR protein recruitment to chromatin is reduced. SiRNA knockdown; Western blot; p21 PCNA-binding mutant analysis; chromatin fractionation; PCNA Co-IP The Journal of biological chemistry Medium 21725088
2010 CRL4(CDT2)-mediated substrate degradation requires two elements in the substrate PIP box: TD amino acid residues within the PIP box and a basic amino acid at +4 (and +3) downstream of the PIP box. An acidic amino acid following these basic residues abolishes degradation. Introducing all required elements into ligase I peptide renders it degradable. Chimera constructs of CDT1 and Ligase I; mutagenesis; degradation assays in HeLa cells; electrostatic surface analysis Genes to cells : devoted to molecular & cellular mechanisms High 21143559
2013 SCF(FBXO11)/CRL1 interacts with CDT2 and recruits it for proteasomal degradation, thereby restraining CRL4(CDT2) activity. CDK-mediated phosphorylation of CDT2 at Thr464 inhibits recognition by FBXO11. This cross-regulation between SCF(FBXO11) and CRL4(CDT2) is evolutionarily conserved from worms to humans and regulates timing of cell-cycle exit. Affinity purification/mass spectrometry; Co-IP; CDT2 Thr464 mutagenesis; degradation assays; C. elegans epistasis Molecular cell High 23478441 23478445
2013 CDT2 undergoes autoubiquitylation by CRL4A E3 ubiquitin ligase, and is additionally polyubiquitylated and degraded by CRL1(FBXO11). CRL1(FBXO11)-mediated degradation of CDT2 stabilizes p21 and Set8, which is important during TGF-β response—Set8 induction turns off Smad2 activation. CDT2 downregulation via CRL1(FBXO11) also stimulates epithelial cell migration. Co-IP; in vitro ubiquitination assay; siRNA knockdown; TGF-β signaling assays; cell migration assays Molecular cell High 23478441 23478445
2013 CRL4(CDT2) promotes degradation of the DNA repair helicase FBH1 after DNA damage in a PCNA- and PIP-degron-dependent manner. FBH1's anti-recombinase activity is partially dependent on its interaction with PCNA. Degradation of FBH1 by CDT2-proteasome pathway facilitates TLS polymerase eta recruitment to chromatin in UV-irradiated cells. SiRNA knockdown; non-degradable FBH1 mutant expression; Co-IP; immunofluorescence; chromatin fractionation Nucleic acids research Medium 23677613
2013 CRL4(CDT2) regulates the subunit composition of DNA polymerase delta (Pol δ) by targeting the p12 subunit for degradation in response to DNA damage and during S phase entry. The p12 subunit possesses a PIP-degron. Knockdown of CUL4A or CUL4B inhibits p12 degradation. Mutation of the p12 PIP-degron prevents its S phase reduction. SiRNA knockdown; PIP-degron mutagenesis; laser scanning cytometry; Western blot; cell synchronization The Journal of biological chemistry Medium 23913683
2014 14-3-3 adaptor proteins interact with CDT2 phosphorylated at Thr464 and shield CDT2 from polyubiquitination and proteasomal degradation by FbxO11. Depletion of 14-3-3 proteins promotes FbxO11–CDT2 interaction. The stabilization of CDT2 by 14-3-3 proteins is important for cell cycle progression; depletion of 14-3-3γ leads to G2/M delay partly due to Set8 accumulation. Co-IP; phospho-mimicking/blocking CDT2 mutations (T464D/T464A); siRNA knockdown; ubiquitination assay; cell cycle analysis Molecular and cellular biology Medium 25154416
2015 CRL4(CDT2) promotes degradation of XPG endonuclease after its action on bulky DNA lesions (UV, cisplatin) during nucleotide excision repair. CDT2 is recruited to UV-damage sites and interacts with XPG in the presence of PCNA. CDT2-mediated XPG degradation is required for subsequent DNA polymerase delta recruitment and gap-filling DNA synthesis (completion of NER). SiRNA knockdown; micropore UV irradiation; in situ Proximity Ligation Assay; immunofluorescence; DNA repair synthesis assay Cell cycle (Georgetown, Tex.) Medium 25483071
2015 CUL4-DDB1-CDT2 E3 ligase ubiquitinates CRY1 and promotes its degradation in vitro and in vivo. Depletion of DDB1, CDT2, or PCNA leads to CRY1 stabilization in cultured cells and mouse liver. CUL4A-DDB1-CDT2 targets lysine 585 of CRY1, as the CRY1-K585A mutant is resistant to this ubiquitination/degradation. CDT2 depletion or CRY1-K585A overexpression enhances the amplitude of circadian Bmal1 promoter oscillations. In vitro ubiquitination assay; siRNA knockdown; CRY1-K585A mutagenesis; mouse liver experiments; luciferase circadian reporter assay PloS one High 26431207
2012 ATR kinase phosphorylates CDT2 at S/TQ sites following UV irradiation, and this promotes rapid CDT1 degradation. CDT1 degradation is attenuated by caffeine and in ATR-depleted cells but not in ATM-depleted cells. ATR phosphorylates CDT2 in vitro, mostly in the C-terminal region. In vitro kinase assay; siRNA knockdown of ATR/ATM; caffeine inhibition; phosphorylation site mapping; Western blot PloS one Medium 23029527
2018 CDT2 bears a C-terminal PIP box (Cdt2PIP) that directly binds PCNA with two orders of magnitude higher affinity than the CDT1 PIP box. X-ray crystallographic structures of PCNA bound to Cdt2PIP and Cdt1PIP show peptides occupying all three binding sites of the trimeric PCNA ring. Mutating Cdt2PIP reduces PCNA interaction, impairs CRL4CDT2 ubiquitination of Cdt1, and leads to CDT1 degradation defects. X-ray crystallography; in vitro binding assays; site-directed mutagenesis of Cdt2PIP; in vitro ubiquitination assay; cellular CDT1 degradation assay Life science alliance High 30623174
2018 CDT2 contains a conserved C-terminal PIP box-like region required for direct interaction with PCNA. Deletion or mutation of this region abolishes CDT2-PCNA interaction in vitro and in vivo and impairs PCNA-dependent CDT1 degradation in response to DNA damage and during the cell cycle. Recombinant protein expression; site-directed mutagenesis; Co-IP in vitro and in vivo; Western blot The Journal of biological chemistry Medium 30301766
2018 CDK-mediated phosphorylation of CDT2 (at multiple CDK consensus sites in the C-terminal region) inactivates CRL4(CDT2) by reducing CDT2 affinity for PCNA. Mutation of 18 CDK phosphorylation sites (Cdt2-18A) increases CDT2 affinity for PCNA, enhances co-localization with PCNA foci in S phase, increases poly-ubiquitination of CDT1, and prevents accumulation of Set8 and TDG in late S/G2 phase. In vitro phosphorylation assay (cyclinA/Cdk2, cyclinB/Cdk1); CDT2-18A mutagenesis; Co-IP; immunofluorescence; Western blot; cell synchronization Genes to cells : devoted to molecular & cellular mechanisms High 29424068
2018 CRL4(DCAF2/CDT2) in dendritic cells regulates NIK stability by promoting NIK polyubiquitination and degradation independently of TRAF3 degradation. DCAF2 deficiency leads to NIK accumulation and RelB nuclear translocation, resulting in increased IL-23 production. DCAF2 DC-conditional knockout mice display increased sensitivity to autoimmune/psoriatic disease. Conditional knockout mice; DCAF2 depletion; Co-IP; in vivo ubiquitination assay; transcriptomic analysis; immunological assays The Journal of experimental medicine High 30018073
2018 CRL4DCAF2 controls M phase exit in activated T cells. DCAF2 expression is induced upon TCR stimulation. Continuous H4K20me1 modification caused by DCAF2 deficiency inhibits Aurkb expression, which regulates 26S proteasome activity during G2/M phase, causing M phase arrest through proteasome-dependent mechanisms. T cell-specific conditional knockout mice; TCR stimulation assays; Western blot; H4K20me1 ChIP; proteasome activity assays; cell cycle analysis Journal of autoimmunity Medium 30245026
2019 DTL promotes ubiquitin-dependent degradation of the tumor suppressor PDCD4. DTL physically interacts with PDCD4 (confirmed by Co-IP and immunofluorescence), DTL overexpression accelerates PDCD4 degradation, and in vitro ubiquitination assays demonstrate PDCD4 is degraded through DTL-mediated ubiquitination. Affinity-purification mass spectrometry; Co-IP; immunofluorescence; in vitro ubiquitination assay; Western blot; rescue experiments Journal of experimental & clinical cancer research : CR Medium 31409387
2019 The C-terminal region of CDT2 contains a DNA-binding domain that enhances CRL4(CDT2) ubiquitin ligase activity. This domain binds double-stranded and single-stranded DNA. Deletion of this domain impairs UV-irradiation-induced CDT1 polyubiquitination and degradation. The N-terminal WD40 region is sufficient for CRL4 complex formation but not full ligase activity. Deletion and mutation analysis; DNA-binding assays; in vitro ubiquitination assay; cellular CDT1 degradation assay Journal of biochemistry Medium 30649446
2021 CRL4A-DTL ligase complex targets DNA-PKcs for nuclear degradation. Overexpression of CUL4A or DTL reduces NHEJ repair efficiency, increases DSB accumulation, and promotes genomic instability and malignant proliferation in normal cells. In human precancerous lesions, CUL4A expression is negatively correlated with DNA-PKcs. Co-IP; Western blot; NHEJ repair assay; overexpression in normal cells; xenograft; immunohistochemistry Oncogene Medium 33627782
2021 DDB2 mediates ubiquitination and degradation of CDT2 in a PCNA-independent manner (PIP box of DDB2 is dispensable for CDT2 degradation). Knockdown of DDB2 stabilizes CDT2; overexpression of DDB2 enhances CDT2 ubiquitination and degradation. DDB2-mediated CDT2 degradation indirectly regulates CDT1 protein stability and pre-replication complex assembly. Co-IP; in vivo ubiquitination assay; siRNA knockdown; overexpression; PIP box mutagenesis; Western blot; FACS Cell & bioscience Medium 33557942
2017 DCAF2 (DTL/CDT2) is a maternal factor essential for genome stability during the first zygotic cell cycle. Dcaf2 knockout in oocytes leads to female infertility; embryos derived from Dcaf2-null oocytes arrest at the 1-2 cell stage with prolonged DNA replication and massive DNA damage accumulation (rereplication). Oocyte-specific conditional knockout mice (Dcaf2fl/fl with Cre); embryo development analysis; DNA damage markers; Western blot Journal of cell science High 28818995
2021 CRL4(CDT2) ubiquitinates RUVBL1 (pontin/TIP49), promoting its binding to RUVBL2 and to transcription cofactor β-catenin while attenuating its binding to acetyltransferase TIP60. Ubiquitinated RUVBL1 promotes transcriptional regulation of NHEJ repair pathway genes via RUVBL1/2-β-catenin, attenuates TIP60-mediated H4K16 acetylation, and enhances radiation resistance in breast cancer cells. Co-IP; ubiquitination assay; Western blot; rescue experiments; in vitro and in vivo radioresistance assays Cell death & disease Medium 38609375
2023 DCAF14 controls CDT2 activity at stalled replication forks to protect nascent DNA. Absence of DCAF14 increases proteasomal degradation of CDT2 substrates (CDT1, p21, SET8). At stalled forks, increased CDT2 function causes fork collapse; this is dependent on CDT2 substrate SET8, which blocks nuclease-mediated digestion of nascent DNA. SiRNA knockdown; replication fork protection assay; Western blot; rescue experiments with SET8 Life science alliance Medium 37940188
2025 Cryo-EM structures of the DCAF2:DDB1:DDA1 complex (3.3 Å), a ligand-bound complex (3.1 Å), and a ternary complex with a covalent PROTAC and BRD4 (3.4 Å) reveal PROTAC-mediated substrate recruitment to DCAF2. CDT2 residue C141 in the WD40 domain engages covalent ligands. DCAF2 demonstrates robust ubiquitination activity in biochemical assays upon covalent PROTAC engagement. Cryo-EM structure determination; in vitro ubiquitination assay; cellular TPD (COFFEE method); covalent compound engagement at C141 Structure (London, England : 1993) High 41045927
2025 TRIM22 is a novel E3 ubiquitin ligase for CDT2 degradation. In HPV-positive cervical cancer cells, E7-mediated Rb degradation upregulates E2F1, which increases CDT2 transcription; E6-mediated p53 degradation downregulates TRIM22, leading to CDT2 accumulation. CDT2 depletion induces DNA aneuploidy and senescence via stabilization of SET8. Co-IP; Western blot; siRNA knockdown; chromatin immunoprecipitation; ubiquitination assays; cell senescence assays Neoplasia (New York, N.Y.) Medium 40680432
2025 Mdm2 promotes proteasomal degradation of CDT2 (independently of p53), thereby attenuating CRL4(CDT2) activity. Mdm2-mediated CDT2 degradation stabilizes p21, Set8, and CDT1 at the G2/M phase. Loss of Mdm2 causes G2/M delay and decreased proliferation largely through increased CDT2 and subsequent decreased p21 levels. SiRNA/overexpression experiments; Western blot; ubiquitination assays; cell cycle analysis bioRxivpreprint Low bio_10.1101_2025.07.09.663887
2024 DCAF2 maintains proliferation and differentiation of progenitor spermatogonia by targeting p21 and thymine DNA glycosylase (TDG) for degradation during S phase. Germ cell-specific Dcaf2 knockout causes accumulation of p21 and TDG, reduced cell proliferation, increased DNA damage, apoptosis, failure of meiosis initiation, and male infertility. Germ cell-specific conditional knockout mice (Dcaf2fl/fl x Stra8-Cre); Western blot; immunofluorescence; overexpression of p21/TDG; apoptosis assays Cell proliferation High 38837535
2025 DTL mediates K48-linked ubiquitination and proteasomal degradation of SMAD4 in pancreatic cancer cells. This activates the Wnt/β-catenin pathway to promote tumorigenesis. Knockdown of DTL suppresses tumor growth and metastasis in vivo. Co-IP; in vitro ubiquitination assay (K48 linkage); Western blot; siRNA knockdown; xenograft model International journal of biological macromolecules Medium 41203163
2024 Under hypoxia, HIF-1α transcriptionally activates DTL expression. DTL then promotes ubiquitination and degradation of SLTM (SAFB-like transcription modulator), relieving transcriptional repression of Notch1 and activating the Notch pathway to promote HCC proliferation, metastasis, and sorafenib resistance. RNA-sequencing; Co-IP; ubiquitination assay; Western blot; ChIP; orthotopic tumor model; siRNA knockdown Cell death & disease Medium 39384740
2024 DTL promotes K11-linked ubiquitination-mediated degradation of ARGLU1 in head and neck squamous cell carcinoma. This activates the CSL-dependent Notch signaling pathway. siARGLU1 blocks the inhibitory effects of DTL knockdown on HNSCC cells. Mass spectrometry; Co-IP; ubiquitination assay (K11 linkage); siRNA rescue experiments; in vivo tumor growth assay International journal of biological macromolecules Medium 38218284
2025 DTL ubiquitinates and degrades PROX1 in hepatocytes during ischemia/reperfusion injury. DTL-mediated PROX1 degradation increases polyunsaturated fatty acid (PUFA) levels, triggering ferroptosis and exacerbating hepatic I/R injury. Sex-specific differential DTL expression in mice determines sex disparity of I/R-induced ferroptosis. Multi-omics analysis; Co-IP; ubiquitination assay; Western blot; in vivo I/R mouse model; ferroptosis markers Cell reports Medium 40560731

Source papers

Stage 0 corpus · 95 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 540 16949367
2010 Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage. Molecular cell 204 21035370
2011 Mechanism of CRL4(Cdt2), a PCNA-dependent E3 ubiquitin ligase. Genes & development 195 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 150 22287560
2006 DTL/CDT2 is essential for both CDT1 regulation and the early G2/M checkpoint. Genes & development 141 17085480
2010 CRL4(Cdt2) E3 ubiquitin ligase monoubiquitinates PCNA to promote translesion DNA synthesis. Molecular cell 140 20129063
2011 Control of Drosophila endocycles by E2F and CRL4(CDT2). Nature 130 22037307
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
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
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
2006 DNA damage induces Cdt1 proteolysis in fission yeast through a pathway dependent on Cdt2 and Ddb1. EMBO reports 78 17039252
2013 Ubiquitin E3 ligase CRL4(CDT2/DCAF2) as a potential chemotherapeutic target for ovarian surface epithelial cancer. The Journal of biological chemistry 75 23995842
2006 Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma. Cell cycle (Georgetown, Tex.) 74 17106265
2013 Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase. Molecular cell 70 23478441
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
2018 RANGER-DTL 2.0: rigorous reconstruction of gene-family evolution by duplication, transfer and loss. Bioinformatics (Oxford, England) 65 29688310
2016 Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma. EBioMedicine 61 27333051
2012 CRL4(CDT2) targets CHK1 for PCNA-independent destruction. Molecular and cellular biology 59 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
2013 A novel function of CRL4(Cdt2): regulation of the subunit structure of DNA polymerase δ in response to DNA damage and during the S phase. The Journal of biological chemistry 50 23913683
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
2018 CRL4DCAF2 negatively regulates IL-23 production in dendritic cells and limits the development of psoriasis. The Journal of experimental medicine 39 30018073
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
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
2015 Cdt2-mediated XPG degradation promotes gap-filling DNA synthesis in nucleotide excision repair. Cell cycle (Georgetown, Tex.) 26 25483071
2021 CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation. Oncogene 24 33627782
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 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
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
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
2017 Maternal DCAF2 is crucial for maintenance of genome stability during the first cell cycle in mice. Journal of cell science 19 28818995
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
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 17 38609375
2018 Direct binding of Cdt2 to PCNA is important for targeting the CRL4Cdt2 E3 ligase activity to Cdt1. Life science alliance 17 30623174
2014 The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase. Oncotarget 17 25115388
2024 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 15 39384740
2021 DDB2 regulates DNA replication through PCNA-independent degradation of CDT2. Cell & bioscience 15 33557942
2008 Transcriptional regulation of an evolutionary conserved intergenic region of CDT2-INTS7. PloS one 15 18213392
2021 Human umbilical vein endothelial cells-derived microRNA-203-containing extracellular vesicles alleviate non-small-cell lung cancer progression through modulating the DTL/p21 axis. Cancer gene therapy 13 33558703
2018 CRL4DCAF2 is required for mature T-cell expansion via Aurora B-regulated proteasome activity. Journal of autoimmunity 13 30245026
2018 Proliferating cell nuclear antigen interacts with the CRL4 ubiquitin ligase subunit CDT2 in DNA synthesis-induced degradation of CDT1. The Journal of biological chemistry 13 30301766
1996 Identification of a novel Drosophila melanogaster heat-shock gene, lethal(2)denticleless [l(2)dtl], coding for an 83-kDa protein. Gene 13 8666267
2021 DTL-DephosSite: Deep Transfer Learning Based Approach to Predict Dephosphorylation Sites. Frontiers in cell and developmental biology 12 34249915
2012 Checkpoint kinase ATR phosphorylates Cdt2, a substrate receptor of CRL4 ubiquitin ligase, and promotes the degradation of Cdt1 following UV irradiation. PloS one 12 23029527
2022 DTL promotes melanoma progression through rewiring cell glucose metabolism. Annals of translational medicine 10 35282044
2021 MiR-490-5p Restrains Progression of Gastric cancer through DTL Repression. Gastroenterology research and practice 9 34594374
2018 Mutations at multiple CDK phosphorylation consensus sites on Cdt2 increase the affinity of CRL4Cdt2 for PCNA and its ubiquitination activity in S phase. Genes to cells : devoted to molecular & cellular mechanisms 9 29424068
2013 Non-canonical CRL4A/4B(CDT2) interacts with RAD18 to modulate post replication repair and cell survival. PloS one 9 23555860
2024 DTL promotes head and neck squamous cell carcinoma progression by mediating the degradation of ARGLU1 to regulate the Notch signaling pathway. International journal of biological macromolecules 8 38218284
2022 CRL4Cdt2 Ubiquitin Ligase, A Genome Caretaker Controlled by Cdt2 Binding to PCNA and DNA. Genes 8 35205311
2024 DCAF2 regulates the proliferation and differentiation of mouse progenitor spermatogonia by targeting p21 and thymine DNA glycosylase. Cell proliferation 7 38837535
2023 miR-17 ~ 92 suppresses proliferation and invasion of cervical cancer cells by inhibiting cell cycle regulator Cdt2. Discover oncology 7 37707654
2022 Mice lacking DCAF2 in placenta die at the gastrulation stage. Cell and tissue research 7 35711069
2022 Long non-coding RNA DLGAP1-AS1 modulates the development of non-small-cell lung cancer via the microRNA-193a-5p/DTL axis. Laboratory investigation; a journal of technical methods and pathology 7 36183046
2012 Characterization of null and hypomorphic alleles of the Drosophila l(2)dtl/cdt2 gene: Larval lethality and male fertility. Fly 7 22722696
2025 Structural basis for DCAF2 as a novel E3 ligase for PROTAC-mediated targeted protein degradation. Structure (London, England : 1993) 6 41045927
2022 LncRNA ZFPM2-AS1 drives the progression of nasopharyngeal carcinoma via modulating the downstream miR-3612/DTL signaling. Anti-cancer drugs 6 35276693
2025 DTL dose-dependent control of sex-dimorphic ferroptosis in liver ischemia reperfusion injury. Cell reports 4 40560731
2024 DTL promotes the growth and migration of melanoma cells through the ERK/E2F1/BUB1 axis. Scientific reports 4 39487277
2023 DTL is a Novel Downstream Gene of E2F1 that Promotes the Progression of Hepatocellular Carcinoma. Current cancer drug targets 4 37171007
2023 DCAF14 regulates CDT2 to promote SET8-dependent replication fork protection. Life science alliance 4 37940188
2023 Denticleless E3 ubiquitin protein ligase (DTL) maintains the proliferation and differentiation of epidermis and hair follicles during skin development. Developmental dynamics : an official publication of the American Association of Anatomists 4 38131461
2022 The Distribution of Cytotoxic Necrotizing Factors (CNF-1, CNF-2, CNF-3) and Cytolethal Distending Toxins (CDT-1, CDT-2, CDT-3, CDT-4) in Escherichia coli Isolates Isolated from Extraintestinal Infections and the Determination of their Phylogenetic Relationship by PFGE. International journal of clinical practice 4 36474550
2025 MiR-3202-DTL signaling axis impedes NSCLC malignancy via regulating the ubiquitination-proteasome degradation of p21. Molecular and cellular biochemistry 3 40038150
2023 Circ-DTL sponges miR-758-3p to accelerate cervical cancer malignant progression by regulating DCUN1D1 expression. Journal of biochemical and molecular toxicology 3 37522575
2023 Osteopontin regulates the growth and invasion of liver cancer cells via DTL. Oncology letters 3 37809049
2019 A DNA-binding domain in the C-terminal region of Cdt2 enhances the DNA synthesis-coupled CRL4Cdt2 ubiquitin ligase activity for Cdt1. Journal of biochemistry 3 30649446
2010 The Caenorhabditis elegans CDT-2 ubiquitin ligase is required for attenuation of EGFR signalling in vulva precursor cells. BMC developmental biology 3 20977703
2025 E2F8 Transcriptionally Activates DTL to Promote Endometrial Cancer Progression Via the MAPK Pathway. Reproductive sciences (Thousand Oaks, Calif.) 2 41461624
2023 Epithelial CRL4DCAF2 Is Critical for Maintaining Intestinal Homeostasis Against DSS-Induced Colitis by Regulating the Proliferation and Repair of Intestinal Epithelial Cells. Digestive diseases and sciences 2 37968554
2022 Deciphering Microbial Gene Family Evolution Using Duplication-Transfer-Loss Reconciliation and RANGER-DTL. Methods in molecular biology (Clifton, N.J.) 2 36083451
2025 HBx/DTL Positive Feedback Loop Promotes HBV-Related Hepatocellular Carcinoma Progression. Journal of medical virology 1 40062428
2025 Rewired glycolysis by DTL accelerates oncometabolite L-lactate generation to promote breast cancer progression. Frontiers in oncology 1 40391156
2025 The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells. Neoplasia (New York, N.Y.) 1 40680432
2026 LINC01106 drives gastric cancer progression and tumor immune microenvironment remodeling via the miR-361-3p/DTL axis. Cellular signalling 0 41610966
2026 The role of DTL in maintaining survival of cochlear hair cell and hearing function. Neuroscience 0 42081965
2025 DTL promotes pancreatic cancer progression through ubiquitin-mediated degradation of SMAD4. International journal of biological macromolecules 0 41203163
2024 DCAF2 is essential for the development of uterine epithelia and mouse fertility. Frontiers in cell and developmental biology 0 39364135

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