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Papers In Press, published online ahead of print September 30, 2002
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637
Corresponding Author: skron{at}midway.uchicago.edu
Multiple surveillance pathways maintain genomic integrity in yeast during mitosis. While the cyclin-dependent kinase Cdc28 is a well-established regulator of mitotic progression, evidence for a direct role in mitotic surveillance has been lacking. We have now implicated a conserved sequence in the Cdc28 carboxyl-terminus in maintaining chromosome stability through mitosis. Six temperature-sensitive mutants were isolated via random mutagenesis of 13 carboxyl-terminal residues. These mutants identify a Cdc28 domain necessary for proper mitotic arrest in the face of kinetochore defects or microtubule inhibitors. These chromosome stability-defective cdc28CST mutants inappropriately continue mitosis when the mitotic spindle is disrupted at 23 °C, display high rates of spontaneous chromosome loss at 30 °C and suffer catastrophic aneuploidy at 35 °C. A dosage suppression screen identified Cak1, a kinase known to phosphorylate and activate Cdc28, as a specific high-copy suppressor of cdc28CST temperature sensitivity and chromosome instability. Suppression is independent of Cak1's kinase activity, suggesting that Cak1 may bind to the carboxyl terminus to serve a non-catalytic role in assembly and/or stabilization of active Cdc28 complexes. Significantly, these studies implicate Cdc28 and Cak1 in an essential surveillance function required to maintain genetic stability through mitosis.
J. Biol. Chem, 10.1074/jbc.M207247200
Submitted on July 19, 2002
Revised on September 23, 2002
Accepted on September 30, 2002
An essential function of yeast cyclin-dependent kinase Cdc28 maintains chromosome stability
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