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J. Biol. Chem., Vol. 279, Issue 53, 55499-55505, December 31, 2004

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The Enzymatic Activities of the Werner Syndrome Protein Are Disabled by the Amino Acid Polymorphism R834C^*

Ashwini S. Kamath-Loeb, Piri Welcsh, Maureen Waite, Elinor T. Adman¶, and Lawrence A. Loeb||

From the Gottstein Memorial Cancer Research Laboratory, Departments of Pathology and Biochemistry, Department of Genome Sciences, Division of Medical Genetics, and ^¶Department of Biological Structure, University of Washington, Seattle, Washington 98195

The Werner syndrome protein, WRN, is a member of the RecQ family of DNA helicases. It possesses both 3'5' DNA helicase and 3'5' DNA exonuclease activities. Mutations in WRN are causally associated with a rare, recessive disorder, Werner syndrome (WS), distinguished by premature aging and genomic instability; all are reported to result in loss of protein expression. In addition to WS-linked mutations, single nucleotide polymorphisms, with frequencies that exceed those of WS-associated mutations, are also present in WRN. We have initiated studies to determine if six of these polymorphisms affect the enzymatic activities of WRN. We show that two common polymorphisms, F1074L and C1367R, and two infrequent polymorphisms, Q724L and S1079L, exhibit little change in activity relative to wild-type WRN; the polymorphism, T172P, shows a small but consistent reduction of activity. However, an infrequent polymorphism, R834C, located in the helicase domain dramatically reduces WRN helicase and helicase-coupled exonuclease activity. The structure of the E. coli helicase core suggests that R834 may be involved in interactions with ATP. As predicted, substitution of Arg with Cys interferes with ATP hydrolysis that is absolutely required for unwinding DNA. R834C thus represents the first missense amino acid polymorphism in WRN that nearly abolishes enzymatic activity while leaving expression largely unaffected.

Received for publication, June 25, 2004 , and in revised form, October 14, 2004.

Note Added in Proof—Since the submission of this manuscript, Bohr et al. [Bohr, V. A., Metter, E. J., Harrigan, J. A., von Kobbe, C., Liu, J. L., Gray, M. D., Majumdar, A., Wilson, D. M., III, and Seidman, M. M. (2004) Mech. Ageing Dev. 125, 491–496] have also reported that the polymorphism, C13637, does not alter the helicase or exonuclease activities of WRN.

^* This work was supported by Public Health Services Grant CA77852 from the NCI, National Institutes of Health and by the Department of Defense Breast Cancer Research Program Grant 1702-10615. 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.

^|| To whom correspondence should be addressed: Dept. of Pathology, Box 357705, University of Washington, 1959 NE Pacific St., Seattle, WA 98195. Tel.: 206-543-6015; Fax: 206-543-3967; E-mail: laloeb{at}u.washington.edu.

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