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

TY - JOUR

T1 - Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.

AU - Sørensen, Claus Storgaard

AU - Syljuåsen, Randi G

AU - Falck, Jacob

AU - Schroeder, Tine

AU - Rönnstrand, Lars

AU - Khanna, Kum Kum

AU - Zhou, Bin-Bing

AU - Bartek, Jiri

AU - Lukas, Jiri

N1 - Keywords: Cell Cycle; Cell Cycle Proteins; DNA Replication; DNA-Binding Proteins; Enzyme Activation; Hela Cells; Humans; Kinetics; Models, Biological; Phosphorylation; Protein Kinases; Protein-Serine-Threonine Kinases; Radiation, Ionizing; S Phase; Serine; Signal Transduction; Tumor Cells, Cultured; Tumor Suppressor Proteins; cdc25 Phosphatases

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

M3 - Journal article

C2 - 12676583

SN - 1535-6108

VL - 3

SP - 247

EP - 258

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -