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PMID: 10825192 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Mechanism of caffeine-induced checkpoint override in fission yeast.

Molecular and cellular biology ·Vol. 20 ·No. 12 ·2000-06-00 ·Pages 4288-94

Moser BA, Brondello JM, Baber-Furnari B, Russell P

Abstract

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 G(2)-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.

MeSH Terms
Animals Caffeine/pharmacology Checkpoint Kinase 1 Checkpoint Kinase 2 DNA Damage/drug effects DNA Replication/drug effects DNA-Binding Proteins Endonucleases/genetics,metabolism Mitosis/drug effects,genetics Phosphodiesterase Inhibitors/pharmacology Protein Kinases/genetics,metabolism Protein Serine-Threonine Kinases Schizosaccharomyces/cytology,genetics,metabolism Schizosaccharomyces pombe Proteins Signal Transduction/drug effects,genetics
Chemicals
DNA-Binding Proteins Phosphodiesterase Inhibitors Schizosaccharomyces pombe Proteins Caffeine Protein Kinases Checkpoint Kinase 2 Cds1 protein, S pombe Checkpoint Kinase 1 Chk1 protein, S pombe Protein Serine-Threonine Kinases Endonucleases rad1 protein, S pombe
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Moser B A
Departments of Molecular Biology and Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Brondello J M
Baber-Furnari B
Russell P
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.12.4288-4294.2000
Published
2000-06-00
Pages
4288-94
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85796
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.20.12.4288-4294.2000 PMC Full Text View journal details
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