Thymine DNA glycosylase is a CRL4Cdt2 substrate

Tamara J. Slenn, Benjamin Morris, Courtney G. Havens, Robert M. Freeman, Tatsuro S. Takahashi, Johannes C. Walter

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The E3 ubiquitin ligase CRL4Cdt2 targets proteins for destruction in S phase and after DNA damage by coupling ubiquitylation to DNA-bound proliferating cell nuclear antigen (PCNA). Coupling to PCNA involves a PCNA-interacting peptide (PIP) degron motif in the substrate that recruits CRL4Cdt2 while binding to PCNA. In vertebrates, CRL4Cdt2 promotes degradation of proteins whose presence in S phase is deleterious, including Cdt1, Set8, and p21. Here, we show that CRL4Cdt2 targets thymine DNA glycosylase (TDG), a base excision repair enzyme that is involved in DNA demethylation. TDG contains a conserved and nearly perfect match to the PIP degron consensus. TDG is ubiquitylated and destroyed in a PCNA-, Cdt2-, and PIP degron-dependent manner during DNA repair in Xenopus egg extract. The protein can also be destroyed during DNA replication in this system. During Xenopus development, TDG first accumulates during gastrulation, and its expression is down-regulated by CRL4Cdt2. Our results expand the group of vertebrate CRL4Cdt2 substrates to include a bona fide DNA repair enzyme.

Original languageEnglish
Pages (from-to)23043-23055
Number of pages13
JournalJournal of Biological Chemistry
Volume289
Issue number33
DOIs
Publication statusPublished - Aug 15 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Slenn, T. J., Morris, B., Havens, C. G., Freeman, R. M., Takahashi, T. S., & Walter, J. C. (2014). Thymine DNA glycosylase is a CRL4Cdt2 substrate. Journal of Biological Chemistry, 289(33), 23043-23055. https://doi.org/10.1074/jbc.M114.574194