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Originally published In Press as doi:10.1074/jbc.M104975200 on August 13, 2001

J. Biol. Chem., Vol. 276, Issue 41, 38076-38083, October 12, 2001
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Multiple Phosphorylation Sites of DNA Polymerase alpha -Primase Cooperate to Regulate the Initiation of DNA Replication in Vitro*

Oliver SchubDagger §, Gabor Rohaly, Richard W. P. SmithDagger , Annerose SchneiderDagger , Silke Dehde, Irena Dornreiter, and Heinz-Peter NasheuerDagger ||

From the Dagger  Institut für Molekulare Biotechnologie, Abteilung Biochemie, Beutenbergstrasse 11, D-07745 Jena, Germany and the  Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie an der Universität Hamburg, Martinistrasse 52, D-20251 Hamburg, Germany

DNA polymerase alpha -primase (pol-prim) is the only enzyme that can start DNA replication de novo. The 180-kDa (p180) and 68-kDa (p68) subunits of the human four-subunit enzyme are phosphorylated by Cyclin-dependent kinases (Cdks) in a cell cycle-dependent manner. Cyclin A-Cdk2 physically interacts with pol-prim and phosphorylates N-terminal amino acids of the p180 and the p68 subunits, leading to an inhibition of pol-prim in initiating cell-free SV40 DNA replication. Mutation of conserved putative Cdk phosphorylation sites in the N terminus of human p180 and p68 reduced their phosphorylation by Cyclin A-Cdk2 in vitro. In contrast to wild-type pol-prim these mutants were no longer inhibited by Cyclin A-Cdk2 in the initiation of viral DNA replication. Importantly, rather than inhibiting it, Cyclin A-Cdk2 stimulated the initiation activity of pol-prim containing a triple N-terminal alanine mutant of the p180 subunit. Together these results suggest that Cyclin A-Cdk2 executes both stimulatory and inhibitory effects on the activity of pol-prim in initiating DNA replication.

* This work was financially supported by the Deutsche Forschungsgemeinschaft (Na 190/8, Na 190/10, and Na 190/12) and the European Community (CT970125). The Institut für Molekulare Biotechnologie (IMB) and Heinrich-Pette-Institut (HPI) are Gottfried-Wilhelm-Leibniz-Institutes and financially supported by the federal government and by the states of Thüringen and Hamburg.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Dept. of Medical Genetics and Microbiology, Univ. of Toronto, 1 Kings College Cir., Toronto, Ontario M5S 1A8, Canada.

|| To whom correspondence should be addressed. Tel.: 49-3641-65-62-90; Fax: 49-3641-65-62-88; E-mail: nasheuer@imb-jena.de.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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