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Molecular and Cellular Biology, July 1999, p. 4888-4896, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cell Cycle Control of Cdc7p Kinase Activity through Regulation of Dbf4p Stability

Guy Oshiro,1 Julia C. Owens,2 Yiqun Shellman,3 Robert A. Sclafani,3,* and Joachim J. Li4

Molecular Biology Program1 and Department of Biochemistry and Molecular Genetics,3 University of Colorado Health Sciences Center, Denver, Colorado 80262, and Department of Biochemistry2 and Department of Microbiology and Immunology,4 University of California, San Francisco, San Francisco, California 94143-0414

Received 10 November 1998/Returned for modification 17 December 1998/Accepted 8 April 1999

In Saccharomyces cerevisiae, the heteromeric kinase complex Cdc7p-Dbf4p plays a pivotal role at replication origins in triggering the initiation of DNA replication during the S phase. We have assayed the kinase activity of endogenous levels of Cdc7p kinase by using a likely physiological target, Mcm2p, as a substrate. Using this assay, we have confirmed that Cdc7p kinase activity fluctuates during the cell cycle; it is low in the G1 phase, rises as cells enter the S phase, and remains high until cells complete mitosis. These changes in kinase activity cannot be accounted for by changes in the levels of the catalytic subunit Cdc7p, as these levels are constant during the cell cycle. However, the fluctuations in kinase activity do correlate with levels of the regulatory subunit Dbf4p. The regulation of Dbf4p levels can be attributed in part to increased degradation of the protein in G1 cells. This G1-phase instability is cdc16 dependent, suggesting a role of the anaphase-promoting complex in the turnover of Dbf4p. Overexpression of Dbf4p in the G1 phase can partially overcome this elevated turnover and lead to an increase in Cdc7p kinase activity. Thus, the regulation of Dbf4p levels through the control of Dbf4p degradation has an important role in the regulation of Cdc7p kinase activity during the cell cycle.

* Corresponding author. Mailing address: 4200 E. Ninth Ave., Box B121, Denver, CO 80262. Phone: (303) 315-7288. Fax: (303) 315-3326. E-mail: Robert.Sclafani{at}uchsc.edu.

Molecular and Cellular Biology, July 1999, p. 4888-4896, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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