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J. Biol. Chem., Vol. 281, Issue 30, 20865-20872, July 28, 2006

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Mechanism of Stimulation of Human DNA Ligase I by the Rad9-Rad1-Hus1 Checkpoint Complex^*

Wensheng Wang, Laura A. Lindsey-Boltz, Aziz Sancar, and Robert A. Bambara¹

From the Department of Biochemistry & Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642 and the Department of Biochemistry and Biophysics, CB 7260, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599

Accumulating evidence suggests that the Rad9-Rad1-Hus1 (9-1-1) checkpoint complex, known to be a sensor of DNA damage, is also a component of DNA repair systems. Recent results show that 9-1-1 interacts with several base excision repair proteins. It binds the DNA glycosylase MutY homolog, and stimulates DNA polymerase , flap endonuclease 1, and DNA ligase I. 9-1-1 resembles proliferating cell nuclear antigen (PCNA), which stimulates some of these same repair enzymes, and is loaded onto DNA in a similar manner. The complex of 9-1-1 with DNA ligase I can be immunoprecipitated from human cells. Moreover, UV irradiation stimulates 9-1-1·ligase I complex formation, suggesting a role for 9-1-1 in DNA repair. Examining the nature of 9-1-1 interaction with DNA ligase I, we show that there is a similar degree of stimulation on ligation substrates with different structures, and that there is specificity for DNA ligase I. 9-1-1 improves the binding of DNA ligase I to nicked double strand DNA. Furthermore, although high concentrations of casein kinase II strongly inhibits DNA ligase I activity, it does not affect the ability of 9-1-1 to stimulate. This suggests that 9-1-1 is also an activator of DNA ligase I during DNA damage. Unlike PCNA, 9-1-1 stimulates DNA ligase I activity to the same extent on both linear and circular substrates, indicating that encirclement is not a requirement for stimulation. These data are consistent with a direct role for 9-1-1 in DNA repair, but possibly employing a different mechanism than PCNA.

Received for publication, March 10, 2006 , and in revised form, May 18, 2006.

^* This work was supported by National Institutes of Health Grants GM024441(to R. A. B.) and GM322833 (to A. S.). 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 To whom correspondence should be addressed: Box 712, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642. E-mail: robert_bambara{at}urmc.rochester.edu.

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