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J. Biol. Chem., Vol. 279, Issue 18, 18641-18647, April 30, 2004

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Rad9 Protects Cells from Topoisomerase Poison-induced Cell Death^*

David Loegering, Sonnet J. H. Arlander¶, Jennifer Hackbarth¶||, Benjamin T. Vroman¶, Pia Roos-Mattjus||**, Kevin M. Hopkins, Howard B. Lieberman, Larry M. Karnitz, and Scott H. Kaufmann

From the Division of Oncology Research, Mayo Clinic, and Departments of Molecular Pharmacology and ^||Biochemistry/Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, and Center for Radiological Research, Columbia University, New York, New York 10032

Previous studies have suggested two possible roles for Rad9 in mammalian cells subjected to replication stress or DNA damage. One model suggests that a Rad9-containing clamp is loaded onto damaged DNA, where it participates in Chk1 activation and subsequent events that contribute to cell survival. The other model suggests that Rad9 translocates to mitochondria, where it triggers apoptosis by binding to and inhibiting Bcl-2 and Bcl-x_L. To further study the role of Rad9, parental and Rad9^-/- murine embryonic stem (ES) cells were treated with camptothecin, etoposide, or cytarabine, all prototypic examples of three classes of widely used anticancer agents. All three agents induced Rad9 chromatin binding. Each of these agents also triggered S-phase checkpoint activation in parental ES cells, as indicated by a caffeine-inhibitable decrease in [³H]thymidine incorporation into DNA and Cdc25A down-regulation. Interestingly, the ability of cytarabine to activate the S-phase checkpoint was severely compromised in Rad9^-/- cells, whereas activation of this checkpoint by camptothecin and etoposide was unaltered, suggesting that the action of cytarabine is readily distinguished from that of classical topoisomerase poisons. Nonetheless, Rad9 deletion sensitized ES cells to the cytotoxic effects of all three agents, as evidenced by enhanced apoptosis and diminished colony formation. Collectively, these results suggest that the predominant role of Rad9 in ES cells is to promote survival after replicative stress and topoisomerase-mediated DNA damage.

Received for publication, December 10, 2003 , and in revised form, February 24, 2004.

^* This work was supported in part by National Institutes of Health Grants CA73709 (to S. H. K.), CA84321 (to L. M. K.), CA89816 (to H. B. L.), GM52493 (to H. B. L.), and predoctoral fellowships from the Mayo Foundation (to S. J. H. A., J. H., and P. R.-M.). 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.

^¶ These authors contributed equally to this work.

^** Present address: Turku Center for Biotechnology, Fin-20520 Turku, Finland.

Both authors contributed equally to this work. To whom correspondence should be addressed: Div. of Oncology Research, Guggenheim 1301, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905. Tel.: 507-284-8950. Fax: 507-284-3906. E-mail: Kaufmann.Scott{at}Mayo.edu or karnitz.larry{at}mayo.edu.

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