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Published online
doi:10.1083/jcb.200702034
The Journal of Cell Biology, Vol. 178, No. 2, 257-268
The Rockefeller University Press, 0021-9525 $30.00
© Hochegger et al.
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Article

An essential role for Cdk1 in S phase control is revealed via chemical genetics in vertebrate cells



Helfrid Hochegger1, Donniphat Dejsuphong1, Eiichiro Sonoda1, Alihossein Saberi1, Eeson Rajendra2, Jane Kirk3, Tim Hunt3, and Shunichi Takeda1

1 Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
2 The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge CB2 2XZ, England, UK
3 Cancer Research UK, Clare Hall Laboratories, Herts EN6 3LD, England, UK

Correspondence to Helfrid Hochegger: helfrid{at}rg.med.kyoto-u.ac.jp; or Shunichi Takeda: stakeda{at}rg.med.kyoto-u.ac.jp

In vertebrates Cdk1 is required to initiate mitosis; however, any functionality of this kinase during S phase remains unclear. To investigate this, we generated chicken DT40 mutants, in which an analog-sensitive mutant cdk1 as replaces the endogenous Cdk1, allowing us to specifically inactivate Cdk1 using bulky ATP analogs. In cells that also lack Cdk2, we find that Cdk1 activity is essential for DNA replication initiation and centrosome duplication. The presence of a single Cdk2 allele renders S phase progression independent of Cdk1, which suggests a complete overlap of these kinases in S phase control. Moreover, we find that Cdk1 inhibition did not induce re-licensing of replication origins in G2 phase. Conversely, inhibition during mitosis of Cdk1 causes rapid activation of endoreplication, depending on proteolysis of the licensing inhibitor Geminin. This study demonstrates essential functions of Cdk1 in the control of S phase, and exemplifies a chemical genetics approach to target cyclin-dependent kinases in vertebrate cells.

H. Hochegger and D. Dejsuphong contributed equally to this paper.

Abbreviations used in this paper: APC/C, anaphase-promoting complex/cyclosome; cdk1as, Cdk1 analogue sensitive mutant; cdk1-WT, Cdk1-wild type; CHX, cycloheximide; pre-RC, pre-replication complex.


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