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J. Biol. Chem., Vol. 282, Issue 1, 208-215, January 5, 2007

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Cdc7 Is an Active Kinase in Human Cancer Cells Undergoing Replication Stress^*

From the Department of Cell Biology, Nerviano Medical Sciences-Oncology, Via Pasteur 10, 20014 Nerviano, Italy

Cdc7 kinase promotes and regulates DNA replication in eukaryotic organisms. Multiple mechanisms modulating kinase activity in response to DNA replication stress have been reported, supporting the opposing notions that Cdc7 either plays an active role under these conditions or, conversely, is a final target inactivated by a checkpoint response. We have developed new immnunological reagents to study the properties of human Cdc7 kinase in cells challenged with the ribonucleotide reductase inhibitor hydroxyurea or with the DNA topoisomerase II inhibitor etoposide. We show that Cdc7·Dbf4 and Cdc7·Drf1 complexes are stable and active in multiple cell lines upon drug treatment, with Cdc7·Dbf4 accumulating on chromatin-enriched fractions. Cdc7 depletion by small interfering RNA in hydroxyurea and etoposide impairs hyper-phosphorylation of Mcm2 at specific Cdc7-dependent phosphorylation sites and drug-induced hyper-phosphorylation of chromatin-bound Mcm4. Furthermore, sustained inhibition of Cdc7 in the presence of these drugs increases cell death supporting the notion that the Cdc7 kinase plays a role in maintaining cell viability during replication stress.

Received for publication, May 10, 2006 , and in revised form, October 5, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ Current address: Chroma Therapeutics, 93 Milton Park, Abingdon OX14 5RY, United Kingdom.

² To whom correspondence should be addressed. Tel.: 390331581145; Fax: 390331581374; E-mail: corrado.santocanale{at}nervianoms.com.

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