Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress

Liyong Zhang, Chi Hoon Park, Jing Wu, Hyun Kim, Weijun Liu, Takeo Fujita, Manimalha Balasubramani, Emanuel M. Schreiber, Xiao Fan Wang, Yong Wan*

*Corresponding author for this work

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Recent studies have shown a critical function for the ubiquitin-proteasome system (UPS) in regulating the signalling network for DNA damage responses and DNA repair. To search for new UPS targets in the DNA damage signalling pathway, we have carried out a non-biased assay to identify fast-turnover proteins induced by various types of genotoxic stress. This endeavour led to the identification of Rad17 as a protein exhibiting a distinctive pattern of upregulation followed by subsequent degradation after exposure to UV radiation in human primary cells. Our characterization showed that UV-induced Rad17 oscillation is mediated by Cdh1/APC, a ubiquitin-protein ligase. Studies using a degradation-resistant Rad17 mutant demonstrated that Rad17 stabilization prevents the termination of checkpoint signalling, which in turn attenuates the cellular re-entry into cell-cycle progression. The findings provide an insight into how the proteolysis of Rad17 by Cdh1/APC regulates the termination of checkpoint signalling and the recovery from genotoxic stress.

Original languageEnglish (US)
Pages (from-to)1726-1737
Number of pages12
JournalEMBO Journal
Volume29
Issue number10
DOIs
StatePublished - May 19 2010

Keywords

  • Cdh1/APC
  • Checkpoint regulation and carcinogenesis
  • Proteolysis
  • Rad17

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Zhang, L., Park, C. H., Wu, J., Kim, H., Liu, W., Fujita, T., Balasubramani, M., Schreiber, E. M., Wang, X. F., & Wan, Y. (2010). Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress. EMBO Journal, 29(10), 1726-1737. https://doi.org/10.1038/emboj.2010.55