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Molecular and Cellular Biology, June 2000, p. 4288-4294, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mechanism of Caffeine-Induced Checkpoint Override in Fission Yeast

Bettina A. Moser, Jean-Marc Brondello, Beth Baber-Furnari, and Paul Russell*

Departments of Molecular Biology and Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Received 6 October 1999/Returned for modification 30 November 1999/Accepted 16 March 2000

Mitotic checkpoints restrain the onset of mitosis (M) when DNA is incompletely replicated or damaged. These checkpoints are conserved between the fission yeast Schizosaccharomyces pombe and mammals. In both types of organisms, the methylxanthine caffeine overrides the synthesis (S)-M checkpoint that couples mitosis to completion of DNA S phase. The molecular target of caffeine was sought in fission yeast. Caffeine prevented activation of Cds1 and phosphorylation of Chk1, two protein kinases that enforce the S-M checkpoint triggered by hydroxyurea. Caffeine did not inhibit these kinases in vitro but did inhibit Rad3, a kinase that regulates Cds1 and Chk1. In accordance with this finding, caffeine also overrode the G2-M DNA damage checkpoint that requires Rad3 function. Rad3 coprecipitated with Cds1 expressed at endogenous amounts, a finding that supports the hypothesis that Rad3 is involved in direct activation of Cds1.

* Corresponding author. Mailing address: Department of Molecular Biology, Scripps Research Institute, MB-3, 10550 North Torrey Pines Road, La Jolla, CA 92037. Phone: (858) 784-8273. Fax: (858) 784-2265. E-mail: prussell{at}scripps.edu.

Molecular and Cellular Biology, June 2000, p. 4288-4294, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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