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Proteolysis of Rad17 by Cdh1/APC regulates checkpoint termination and recovery from genotoxic stress
Author(s) -
Zhang Liyong,
Park ChiHoon,
Wu Jing,
Kim Hyun,
Liu Weijun,
Fujita Takeo,
Balasubramani Manimalha,
Schreiber Emanuel M,
Wang XiaoFan,
Wan Yong
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.55
Subject(s) - biology , proteolysis , g2 m dna damage checkpoint , cdh1 , genetics , microbiology and biotechnology , cell cycle checkpoint , cancer research , cancer , cell cycle , biochemistry , enzyme , cadherin , cell
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.