Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Cancer Cell |
Volume | 3 |
Issue number | 3 |
Pages (from-to) | 247-58 |
Number of pages | 11 |
ISSN | 1535-6108 |
Publication status | Published - 2003 |
Bibliographical note
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
ID: 5015724