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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zhang, L; Park, C-H; Wu, J; Kim, H; Liu, W; Fujita, T; Balasubramani, M; Schreiber, EM; Wang, X-F; Wan, Y

Published Date

  • May 19, 2010

Published In

Volume / Issue

  • 29 / 10

Start / End Page

  • 1726 - 1737

PubMed ID

  • 20424596

Pubmed Central ID

  • 20424596

Electronic International Standard Serial Number (EISSN)

  • 1460-2075

Digital Object Identifier (DOI)

  • 10.1038/emboj.2010.55

Language

  • eng

Conference Location

  • England