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Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A.
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2003 (English)In: Cancer Cell, ISSN 1535-6108, Vol. 3, no 3, 247-58 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2003. Vol. 3, no 3, 247-58 p.
Keyword [en]
Cell Cycle/*physiology/radiation effects, Cell Cycle Proteins, DNA Replication/radiation effects, DNA-Binding Proteins, Enzyme Activation, Hela Cells, Humans, Kinetics, Models; Biological, Phosphorylation, Protein Kinases/*metabolism, Protein-Serine-Threonine Kinases/physiology, Radiation; Ionizing, S Phase/radiation effects, Serine/metabolism, Signal Transduction, Tumor Cells; Cultured, Tumor Suppressor Proteins, cdc25 Phosphatase/*physiology/radiation effects
Identifiers
URN: urn:nbn:se:uu:diva-10806PubMedID: 12676583OAI: oai:DiVA.org:uu-10806DiVA: diva2:38574
Available from: 2007-04-25 Created: 2007-04-25 Last updated: 2011-01-13

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