ArticleThe Journal of biological chemistry2014
CRL4Cdt2 E3 ubiquitin ligase and proliferating cell nuclear antigen (PCNA) cooperate to degrade thymine DNA glycosylase in S phase.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 54 citations in OpenAlex.
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- Protein-Protein Interactions in Base Excision Repair.Biomolecules · 2025Review
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- DCAF2 regulates the proliferation and differentiation of mouse progenitor spermatogonia by targeting p21 and thymine DNA glycosylase.Cell proliferation · 2024Article
- Molecular glue degrader for tumor treatment.Frontiers in oncology · 2024Review
- Nucleus-localized circSLC39A5 suppresses hepatocellular carcinoma development by binding to STAT1 to regulate TDG transcription.Cancer science · 2023Article
- Ionic strength modulates excision of uracil by SMUG1 from nucleosome core particles.DNA repair · 2023Article
- Revisiting the Function of p21International journal of molecular sciences · 2022Review
- Kinetic Analysis of the Effect ofBiochemistry · 2022Article
- Regulation of DNA Replication Licensing and Re-Replication by Cdt1.International journal of molecular sciences · 2021Review
- SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Focus on DNA Glycosylases-A Set of Tightly Regulated Enzymes with a High Potential as Anticancer Drug Targets.International journal of molecular sciences · 2020Review
- CRL4Cdt2 ubiquitin ligase regulates Dna2 and Rad16 (XPF) nucleases by targeting Pxd1 for degradation.PLoS genetics · 2020Article
- Inducible TDG knockout models to study epigenetic regulation.F1000Research · 2020Article
- Defining the Role of Nucleotide Flipping in Enzyme Specificity UsingJournal of the American Chemical Society · 2019Article
- SUMOylation coordinates BERosome assembly in active DNA demethylation during cell differentiation.The EMBO journal · 2019Article
- The emerging role for Cullin 4 family of E3 ligases in tumorigenesis.Biochimica et biophysica acta. Reviews on cancer · 2019Review
- The Deubiquitinase USP46 Is Essential for Proliferation and Tumor Growth of HPV-Transformed Cancers.Molecular cell · 2018Article
- Nucleosomes and the three glycosylases: High, medium, and low levels of excision by the uracil DNA glycosylase superfamily.DNA repair · 2018Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Thymine DNA glycosylase (TDG) is an essential enzyme playing multiple roles in base excision repair, transcription regulation, and DNA demethylation. TDG mediates the cytotoxicity of the anti-cancer chemotherapeutic drug 5-fluorouracil (5-FU) by prolonging S phase, generating DNA strand breaks, and inducing DNA damage signaling. During S phase of the cell cycle, TDG is degraded via the proteasomal pathway. Here we show that CRL4(Cdt2) E3 ubiquitin ligase promotes ubiquitination and proteasomal degradation of TDG in S phase in a reaction that is dependent on the interaction of TDG with proliferating cell nuclear antigen (PCNA). siRNA-mediated depletion of PCNA or components of CRL4(Cdt2), specifically cullin4A/B or substrate adaptor Cdt2, stabilizes TDG in human cells. Mutations in the PCNA-interacting peptide (PIP) motif of TDG that disrupt the interaction of TDG with PCNA or change critical basic residues essential for the action of the PIP degron prevent the ubiquitination and degradation of TDG. Thus physical interaction of TDG with PCNA through the PIP degron is required for targeting TDG to the CRL4(Cdt2) E3 ubiquitin ligase complex. Compared with forced expression of wild type TDG, CRL4(Cdt2)- resistant TDG (ΔPIP) slows cell proliferation and slightly increases the toxicity of 5-FU. Thus, CRL4(Cdt2)-dependent degradation of TDG occurs in S phase because of the requirement for TDG to interact with chromatin-loaded PCNA, and this degradation is important for preventing toxicity from excess TDG.
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