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Molecular and Cellular Biology, June 2000, p. 3795-3806, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hierarchy of S-Phase-Promoting Factors: Yeast Dbf4-Cdc7 Kinase Requires Prior S-Phase Cyclin-Dependent Kinase Activation

Romain Nougarède,1 Flavio Della Seta,1 Patrick Zarzov,2,dagger and Etienne Schwob1,*

Institute of Molecular Genetics, CNRS UMR 5535 and Université Montpellier II, F-34293 Montpellier cedex 5,1 and Service de Biochimie et de Génétique Moléculaire, CEA/Saclay, F-91191 Gif-sur Yvette,2 France

Received 26 August 1999/Returned for modification 1 November 1999/Accepted 28 February 2000

In all eukaryotes, the initiation of DNA synthesis requires the formation of prereplicative complexes (pre-RCs) on replication origins, followed by their activation by two S-T protein kinases, an S-phase cyclin-dependent kinase (S-CDK) and a homologue of yeast Dbf4-Cdc7 kinase (Dbf4p-dependent kinase [DDK]). Here, we show that yeast DDK activity is cell cycle regulated, though less tightly than that of the S-CDK Clb5-Cdk1, and peaks during S phase in correlation with Dbf4p levels. Dbf4p is short-lived throughout the cell cycle, but its instability is accentuated during G1 by the anaphase-promoting complex. Downregulating DDK activity is physiologically important, as joint Cdc7p and Dbf4p overexpression is lethal. Because pre-RC formation is a highly ordered process, we asked whether S-CDK and DDK need also to function in a specific order for the firing of origins. We found that both kinases are activated independently, but we show that DDK can perform its function for DNA replication only after S-CDKs have been activated. Cdc45p, a protein needed for initiation, binds tightly to chromatin only after S-CDK activation (L. Zou and B. Stillman, Science 280:593-596, 1998). We show that Cdc45p is phosphorylated by DDK in vitro, suggesting that it might be one of DDK's critical substrates after S-CDK activation. Linking the origin-bound DDK to the tightly regulated S-CDK in a dependent sequence of events may ensure that DNA replication initiates only at the right time and place.

* Corresponding author. Mailing address: Institute of Molecular Genetics (IGM), CNRS UMR 5535, 1919 Route de Mende, F-34293 Montpellier cedex 5, France. Phone: 33 467 61 36 79. Fax: 33 467 04 02 31. E-mail: schwob{at}jones.igm.cnrs-mop.fr.

dagger Present address: Imperial Cancer Research Fund (ICRF), London WC2A 3PX, United Kingdom.

Molecular and Cellular Biology, June 2000, p. 3795-3806, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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