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


Autoria(s): Sorensen, Claus Storgaard; Syluasen, Randi G.; Falck, Jacob; Schroeder, Tine; Ronnstrand, Lars; Khanna, Kum Kum; Zhou, Bin-Bing; Bartek, Jiri; Lukas, Jiri
Contribuinte(s)

M. Resnicoff

Data(s)

01/01/2003

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

http://espace.library.uq.edu.au/view/UQ:64980

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