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J. Biol. Chem., Vol. 282, Issue 20, 15114-15125, May 18, 2007

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Mycobacterial UvrD1 Is a Ku-dependent DNA Helicase That Plays a Role in Multiple DNA Repair Events, Including Double-strand Break Repair^*

Krishna Murari Sinha¹, Nicolas C. Stephanou¹, Feng Gao, Michael S. Glickman^¶2, and Stewart Shuman³

From the Molecular Biology and Immunology Programs, Sloan-Kettering Institute and the ^¶Division of Infectious Diseases, Memorial-Sloan Kettering Cancer Center, New York, New York 10021

Mycobacterium tuberculosis and other bacterial pathogens have a Ku-dependent nonhomologous end joining pathway of DNA double-strand break repair. Here we identify mycobacterial UvrD1 as a novel interaction partner for Ku in a genome-wide yeast two-hybrid screen. UvrD1 per se is a vigorous DNA-dependent ATPase but a feeble DNA helicase. Ku stimulates UvrD1 to catalyze ATP-dependent unwinding of 3'-tailed DNAs. UvrD1, Ku, and DNA form a stable ternary complex in the absence of ATP. The Ku binding determinants are located in the distinctive C-terminal segment of UvrD1. A second mycobacterial paralog, UvrD2, is a vigorous Ku-independent DNA helicase. Ablation of UvrD1 sensitizes Mycobacterium smegmatis to killing by ultraviolet and ionizing radiation and to a single chromosomal break generated by I-SceI endonuclease. The physical and functional interactions of bacterial Ku and UvrD1 highlight the potential for cross-talk between components of nonhomologous end joining and nucleotide excision repair pathways.

Received for publication, February 7, 2007 , and in revised form, March 19, 2007.

^* This work was supported by National Institutes of Health Grant AI64693. 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 These authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: glickmam{at}MSKCC.ORG.

³ American Cancer Society Research Professor. To whom correspondence may be addressed. E-mail: s-shuman{at}ski.mskcc.org.

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