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J. Biol. Chem., Vol. 280, Issue 47, 39627-39636, November 25, 2005

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Modulation of Werner Syndrome Protein Function by a Single Mutation in the Conserved RecQ Domain^*

Jae Wan Lee, Rika Kusumoto, Kevin M. Doherty, Guang-Xin Lin, Wangyong Zeng, Wen-Hsing Cheng, Cayetano von Kobbe¶, Robert M. Brosh, Jr., Jin-Shan Hu, and Vilhelm A. Bohr1

From the Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224, ^¶Molecular Pathology Program, Breast and Gynaecological Cancer Group, Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Centre), C/Melchor Fernández Almagro 3, Madrid, 28029, Spain, and the Department of Chemistry and Biochemistry, and the Center for Biomolecular Structure and Organization, University of Maryland, College Park, Maryland 20742

Naturally occurring mutations in the human RECQ3 gene result in truncated Werner protein (WRN) and manifest as a rare premature aging disorder, Werner syndrome. Cellular and biochemical studies suggest a multifaceted role of WRN in DNA replication, DNA repair, recombination, and telomere maintenance. The RecQ C-terminal (RQC) domain of WRN was determined previously to be the major site of interaction for DNA and proteins. By using site-directed mutagenesis in the WRN RQC domain, we determined which amino acids might be playing a critical role in WRN function. A site-directed mutation at Lys-1016 significantly decreased WRN binding to fork or bubble DNA substrates. Moreover, the Lys-1016 mutation markedly reduced WRN helicase activity on fork, D-loop, and Holliday junction substrates in addition to reducing significantly the ability of WRN to stimulate FEN-1 incision activities. Thus, DNA binding mediated by the RQC domain is crucial for WRN helicase and its coordinated functions. Our nuclear magnetic resonance data on the three-dimensional structure of the wild-type RQC and Lys-1016 mutant proteins display a remarkable similarity in their structures.

Received for publication, June 3, 2005 , and in revised form, August 22, 2005.

^* This work was supported by the Intramural Research Program of the NIA, National Institutes of Health. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplements 1 and 2.

¹ To whom correspondence should be addressed: Laboratory of Molecular Gerontology, National Institute on Aging, Box 1, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825. Tel.: 410-558-8162; Fax: 410-558-8157; E-mail: bohrv{at}grc.nia.nih.gov.

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