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J. Biol. Chem., Vol. 282, Issue 31, 22721-22730, August 3, 2007

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A Conserved Physical and Functional Interaction between the Cell Cycle Checkpoint Clamp Loader and DNA Ligase I of Eukaryotes^*

Wei Song, David S. Levin¹, Johnson Varkey, Sean Post², Vladimir P. Bermudez^¶, Jerard Hurwitz^¶, and Alan E. Tomkinson^||3

From the Molecular Medicine Graduate Program and the ^||Radiation Oncology Research Laboratory and Marlene & Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, the Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, Texas 78245, and the ^¶Program in Molecular Biology, Sloan Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

DNA ligase I joins Okazaki fragments during DNA replication and completes certain excision repair pathways. The participation of DNA ligase I in these transactions is directed by physical and functional interactions with proliferating cell nuclear antigen, a DNA sliding clamp, and, replication factor C (RFC), the clamp loader. Here we show that DNA ligase I also interacts with the hRad17 subunit of the hRad17-RFC cell cycle checkpoint clamp loader, and with each of the subunits of its DNA sliding clamp, the heterotrimeric hRad9-hRad1-hHus1 complex. In contrast to the inhibitory effect of RFC, hRad17-RFC stimulates joining by DNA ligase I. Similar results were obtained with the homologous Saccharomyces cerevisiae proteins indicating that the interaction between the replicative DNA ligase and checkpoint clamp is conserved in eukaryotes. Notably, we show that hRad17 preferentially interacts with and specifically stimulates dephosphorylated DNA ligase I. Moreover, there is an increased association between DNA ligase I and hRad17 in S phase following DNA damage and replication blockage that occurs concomitantly with DNA damage-induced dephosphorylation of chromatin-associated DNA ligase I. Thus, our results suggest that the in vivo interaction between DNA ligase I and the checkpoint clamp loader is regulated by post-translational modification of DNA ligase I.

Received for publication, May 8, 2007 , and in revised form, June 6, 2007.

^* This study was supported by National Institutes of Health Grants GM57479 (to A. E. T.), CA92584 (to A. E. T.), and GM034559 (to J. H.). 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 Present address: Eisai, Inc., Teaneck, NJ 07666.

² Present address: Dept. of Molecular Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030.

³ To whom correspondence should be addressed: 655 West Baltimore St., Baltimore, MD 21201. Tel.: 410-706-2365; Fax: 410-706-3000; E-mail: atomkinson{at}som.umaryland.edu.

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