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J. Biol. Chem., Vol. 281, Issue 44, 33276-33282, November 3, 2006

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Repeated Phosphopeptide Motifs in Human Claspin Are Phosphorylated by Chk1 and Mediate Claspin Function^*

From the Department of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Claspin is a checkpoint protein involved in ATR (ataxia telangiectasia mutated- and Rad3-related)-dependent Chk1 activation in Xenopus and human cells. In Xenopus, Claspin interacts with Chk1 after DNA damage through a region containing two highly conserved repeats, which becomes phosphorylated during the checkpoint response. Because this region is also conserved in human Claspin, we investigated the regulation and function of these potential phosphorylation sites in human Claspin. We found that Claspin is phosphorylated in vivo at Thr-916 in response to replication stress and UV damage. Mutation of these phosphorylation sites on Claspin inhibited Claspin-Chk1 interaction in vivo, impaired Chk1 activation, and induced premature chromatin condensation in cells, indicating a defect in replication checkpoint. In addition, we found that Thr-916 on Claspin is phosphorylated by Chk1, suggesting that Chk1 regulates Claspin during checkpoint response. These results together indicate that phosphorylation of Claspin repeats in human Claspin is important for Claspin function and the regulation of Claspin-Chk1 interaction in human cells.

Received for publication, May 8, 2006 , and in revised form, September 7, 2006.

^* This work was supported in part by Grants CA89239, CA92312, and CA100109 from the National Institutes of Health. 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.

¹ Recipient of U. S. Department of Defense Breast Cancer Career Development Award DAMD 17-02-1-0472. To whom correspondence should be addressed: Dept. of Therapeutic Radiology, Hunter Bldg., Rm. 213C, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520. Tel.: 203-785-2967; Fax: 203-785-7482; E-mail: Junjie.Chen{at}yale.edu.

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