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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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