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Science 5 November 1999:
Vol. 286. no. 5442, pp. 1166 - 1171
DOI: 10.1126/science.286.5442.1166
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Reports

Control of the DNA Damage Checkpoint by Chk1 and Rad53 Protein Kinases Through Distinct Mechanisms

Yolanda Sanchez, 12*dagger Jeff Bachant, 12* Hong Wang, 12 Fenghua Hu, 12 Dou Liu, 12 Michael Tetzlaff, 13 Stephen J. Elledge 123ddagger

In response to DNA damage, cells activate checkpoint pathways that prevent cell cycle progression. In fission yeast and mammals, mitotic arrest in response to DNA damage requires inhibitory Cdk phosphorylation regulated by Chk1. This study indicates that Chk1 is required for function of the DNA damage checkpoint in Saccharomyces cerevisiae but acts through a distinct mechanism maintaining the abundance of Pds1, an anaphase inhibitor. Unlike other checkpoint mutants, chk1 mutants were only mildly sensitive to DNA damage, indicating that checkpoint functions besides cell cycle arrest influence damage sensitivity. Another kinase, Rad53, was required to both maintain active cyclin-dependent kinase 1, Cdk1(Cdc28), and prevent anaphase entry after checkpoint activation. Evidence suggests that Rad53 exerts its role in checkpoint control through regulation of the Polo kinase Cdc5. These results support a model in which Chk1 and Rad53 function in parallel through Pds1 and Cdc5, respectively, to prevent anaphase entry and mitotic exit after DNA damage. This model provides a possible explanation for the role of Cdc5 in DNA damage checkpoint adaptation.

1 Howard Hughes Medical Institute,
2 Verna and Marrs McLean Department of Biochemistry, and
3 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
*   These authors contributed equally to this work.

dagger    Present address: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524, USA.

ddagger    To whom all correspondence should be addressed. E-mail: selledge{at}bcm.tmc.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)