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

Sorensen, Claus Storgaard; Syljuasen, Randi G; Falck, Jacob; Schroeder, Tine; Rönnstrand, Lars LU ; Khanna, Kum Kum; Zhou, Bin-Bing; Bartek, Jiri and Lukas, Jiri (2003) In Cancer Cell 3(3). p.247-258
Abstract
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... (More)
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. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Cell
volume
3
issue
3
pages
247 - 258
publisher
Cell Press
external identifiers
  • pmid:12676583
  • scopus:0012966157
ISSN
1878-3686
DOI
10.1016/S1535-6108(03)00048-5
language
English
LU publication?
no
id
be9b0ba3-10c8-4034-b9a8-9ca686e4eedf (old id 1126210)
date added to LUP
2008-06-11 13:34:58
date last changed
2017-09-03 03:50:05
@article{be9b0ba3-10c8-4034-b9a8-9ca686e4eedf,
  abstract     = {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.},
  author       = {Sorensen, Claus Storgaard and Syljuasen, Randi G and Falck, Jacob and Schroeder, Tine and Rönnstrand, Lars and Khanna, Kum Kum and Zhou, Bin-Bing and Bartek, Jiri and Lukas, Jiri},
  issn         = {1878-3686},
  language     = {eng},
  number       = {3},
  pages        = {247--258},
  publisher    = {Cell Press},
  series       = {Cancer Cell},
  title        = {Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A},
  url          = {http://dx.doi.org/10.1016/S1535-6108(03)00048-5},
  volume       = {3},
  year         = {2003},
}