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J. Biol. Chem., Vol. 283, Issue 12, 7590-7598, March 21, 2008

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Regulation of WRN Protein Cellular Localization and Enzymatic Activities by SIRT1-mediated Deacetylation^*

Kai Li¹, Alex Casta¹, Rui Wang¹, Enerlyn Lozada^¶, Wei Fan, Susan Kane^||, Qingyuan Ge^||, Wei Gu, David Orren^¶, and Jianyuan Luo, Supported by an AFAR research grant while this work was conducted²

From the Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, the Institute for Cancer Genetics, Columbia University, New York, New York 10032, the ^¶Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536-0305, and ^||Cell Signaling Technology, Danvers, Massachusetts 01923

Werner syndrome is an autosomal recessive disorder associated with premature aging and cancer predisposition caused by mutations of the WRN gene. WRN is a member of the RecQ DNA helicase family with functions in maintaining genome stability. Sir2, an NAD-dependent histone deacetylase, has been proven to extend life span in yeast and Caenorhabditis elegans. Mammalian Sir2 (SIRT1) has also been found to regulate premature cellular senescence induced by the tumor suppressors PML and p53. SIRT1 plays an important role in cell survival promoted by calorie restriction. Here we show that SIRT1 interacts with WRN both in vitro and in vivo; this interaction is enhanced after DNA damage. WRN can be acetylated by acetyltransferase CBP/p300, and SIRT1 can deacetylate WRN both in vitro and in vivo. WRN acetylation decreases its helicase and exonuclease activities, and SIRT1 can reverse this effect. WRN acetylation alters its nuclear distribution. Down-regulation of SIRT1 reduces WRN translocation from nucleoplasm to nucleoli after DNA damage. These results suggest that SIRT1 regulates WRN-mediated cellular responses to DNA damage through deacetylation of WRN.

Received for publication, November 28, 2007 , and in revised form, January 17, 2008.

^* This work was supported in part by a grant from the Worcester Foundation Annual Research Award (to J. L.) and NCI, National Institutes of Health Grant R01 CA113371 (to D. O. and E. L.). 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 supplemental Fig. S1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Cancer Biology, University of Massachusetts Medical School, 422 LRB, 364 Plantation St., Worcester, MA 01605. Tel.: 508-856-4437; Fax: 508-856-1310; E-mail: Jianyuan.luo{at}umassmed.edu.

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