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J Biol Chem. 2014 Aug 15;289(33):23043-55. doi: 10.1074/jbc.M114.574194. Epub 2014 Jun 19.

Thymine DNA glycosylase is a CRL4Cdt2 substrate.

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  • 1From the Departments of Biological Chemistry and Molecular Pharmacology and.
  • 2Systems Biology, Harvard Medical School, Boston, Massachusetts 02115.
  • 3the Graduate School of Science, Osaka University, Osaka, Japan, and.
  • 4From the Departments of Biological Chemistry and Molecular Pharmacology and the Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts 02115 johannes_walter@hms.harvard.edu.

Abstract

The E3 ubiquitin ligase CRL4(Cdt2) 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 CRL4(Cdt2) while binding to PCNA. In vertebrates, CRL4(Cdt2) promotes degradation of proteins whose presence in S phase is deleterious, including Cdt1, Set8, and p21. Here, we show that CRL4(Cdt2) 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 CRL4(Cdt2). Our results expand the group of vertebrate CRL4(Cdt2) substrates to include a bona fide DNA repair enzyme.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

Base Excision Repair (BER); CRL4-Cdt2; DNA Methylation; DNA Replication; E3 Ubiquitin Ligase; Proteolysis; Thymine DNA Glycosylase (TDG); Xenopus

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