Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A
Contribuinte(s) |
M. Resnicoff |
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Data(s) |
01/01/2003
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Resumo |
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. |
Identificador | |
Idioma(s) |
eng |
Publicador |
Cell Press |
Palavras-Chave | #Oncology #Cell-cycle Progression #Dna-damage Checkpoint #Xenopus Egg Extracts #Ataxia-telangiectasia #Protein-kinase #Microsatellite Instability #Endometrial Cancers #Atm #Replication #Pathways #11 Medical and Health Sciences #1112 Oncology and Carcinogenesis |
Tipo |
Journal Article |