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J. Biol. Chem., Vol. 283, Issue 16, 10764-10772, April 18, 2008

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Two DNA-binding and Nick Recognition Modules in Human DNA Ligase III^*

Elizabeth Cotner-Gohara, In-Kwon Kim, Alan E. Tomkinson^¶, and Tom Ellenberger¹

From the Biological and Biomedical Sciences Program, Harvard Medical School, Boston, Massachusetts 02115, the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, and the ^¶Radiation Oncology Research Laboratory, Department of Radiation Oncology, School of Medicie, University of Maryland, Baltimore, Maryland 21201

Human DNA ligase III contains an N-terminal zinc finger domain that binds to nicks and gaps in DNA. This small domain has been described as a DNA nick sensor, but it is not required for DNA nick joining activity in vitro. In light of new structural information for mammalian ligases, we measured the DNA binding affinity and specificity of each domain of DNA ligase III. These studies identified two separate, independent DNA-binding modules in DNA ligase III that each bind specifically to nicked DNA over intact duplex DNA. One of these modules comprises the zinc finger domain and DNA-binding domain, which function together as a single DNA binding unit. The catalytic core of ligase III is the second DNA nick-binding module. Both binding modules are required for ligation of blunt ended DNA substrates. Although the zinc finger increases the catalytic efficiency of nick ligation, it appears to occupy the same binding site as the DNA ligase III catalytic core. We present a jackknife model for ligase III that posits conformational changes during nick sensing and ligation to extend the versatility of the enzyme.

Received for publication, October 2, 2007 , and in revised form, January 22, 2008.

^* This work was supported by Structural Biology of DNA Repair Program Project Grant P01 CA092584 and National Institutes of Health Grants GM52504 (to T. E.) and ES12512 (to A. E. T.). 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: 660 S. Euclid Ave., Campus Box 8231, St. Louis, MO 63110. Tel.: 314-747-8893; Fax: 314-362-4432; E-mail: tome{at}biochem.wustl.edu.

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