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Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A

På svenska

Author

  • Claus Storgaard Sorensen
  • Randi G Syljuasen
  • Jacob Falck
  • Tine Schroeder
  • Lars Rönnstrand
  • Kum Kum Khanna
  • Bin-Bing Zhou
  • Jiri Bartek
  • Jiri Lukas

Summary, in English

Chk1 kinase coordinates cell cycle progression and preserves genome integrity. Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase-promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A, and caused radioresistant DNA synthesis (RDS). The basal turnover of Cdc25A operating in unperturbed S phase required Chk1-dependent phosphorylation of serines 123, 178, 278, and 292. IR-induced acceleration of Cdc25A proteolysis correlated with increased phosphate incorporation into these residues generated by a combined action of Chk1 and Chk2 kinases. Finally, phosphorylation of Chk1 by ATM was required to fully accelerate the IR-induced degradation of Cdc25A. Our results provide evidence that the mammalian S phase checkpoint functions via amplification of physiologically operating, Chk1-dependent mechanisms.

Publishing year

2003

Language

English

Pages

247-258

Publication/Series

Cancer Cell

Volume

3

Issue

3

Document type

Journal article

Publisher

Cell Press

Topic

  • Cancer and Oncology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1878-3686