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J. Biol. Chem., Vol. 279, Issue 53, 55196-55201, December 31, 2004

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A Conserved Interaction between the Replicative Clamp Loader and DNA Ligase in Eukaryotes

IMPLICATIONS FOR OKAZAKI FRAGMENT JOINING^*

David S. Levin¶, Sangeetha Vijayakumar||¶, Xiuping Liu**, Vladimir P. Bermudez, Jerard Hurwitz, and Alan E. Tomkinson¶¶

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

The recruitment of DNA ligase I to replication foci and the efficient joining of Okazaki fragments is dependent on the interaction between DNA ligase I and proliferating cell nuclear antigen (PCNA). Although the PCNA sliding clamp tethers DNA ligase I to nicked duplex DNA circles, the interaction does not enhance DNA joining. This suggests that other factors may be involved in the joining of Okazaki fragments. In this study, we describe an association between replication factor C (RFC), the clamp loader, and DNA ligase I in human cell extracts. Subsequently, we demonstrate that there is a direct physical interaction between these proteins that involves both the N- and C-terminal domains of DNA ligase I, the N terminus of the large RFC subunit p140, and the p36 and p38 subunits of RFC. Although RFC inhibited DNA joining by DNA ligase I, the addition of PCNA alleviated inhibition by RFC. Notably, the effect of PCNA on ligation was dependent on the PCNA-binding site of DNA ligase I. Together, these results provide a molecular explanation for the key in vivo role of the DNA ligase I/PCNA interaction and suggest that the joining of Okazaki fragments is coordinated by pairwise interactions among RFC, PCNA, and DNA ligase I.

Received for publication, August 12, 2004 , and in revised form, October 19, 2004.

^* This work was supported by National Institutes of Health Grants GM57479 (to A. E. T.) and GM38559 (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.

Present address: GeneTex Inc., 14785 Omicron Dr., San Antonio, TX 78245.

^¶ These authors contributed equally.

^** Present address: Dept. of Molecular Genetics, M. D. Anderson Cancer Center, University of Texas, Houston, TX 77030.

^¶¶ To whom correspondence should be addressed: Radiation Oncology Research Laboratory, Dept. of Radiation Oncology and Greenebaum Cancer Center, University of Maryland School of Medicine, 655 W. Baltimore St., Baltimore, MD 21201. Tel.: 410-706-2365; Fax: 410-706-3000; E-mail: atomkinson{at}som.umaryland.edu.

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