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J. Biol. Chem., Vol. 279, Issue 51, 53465-53474, December 17, 2004

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Regulation of WRN Helicase Activity in Human Base Excision Repair^*

Byungchan Ahn, Jeanine A. Harrigan, Fred E. Indig, David M. Wilson, III, and Vilhelm A. Bohr¶

From the Department of Life Sciences, University of Ulsan, Ulsan 680-749, Korea and Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224

Werner syndrome patients are deficient in the Werner protein (WRN), which is a multifunctional nuclear protein possessing 3'–5' exonuclease and ATP-dependent helicase activities. Studies of Werner syndrome cells and biochemical studies of WRN suggest that WRN plays a role in several DNA metabolic pathways. WRN interacts with DNA polymerase (pol ) and stimulates pol strand displacement synthesis on a base excision repair (BER) intermediate in a helicase-dependent manner. In this report, we examined the effect of the major human apurinic/apyrimidinic endonuclease (APE1) and of pol on WRN helicase activity. The results show that WRN alone is able to unwind several single strand break BER intermediates. However, APE1 inhibits WRN helicase activity on these intermediates. This inhibition is likely due to the binding of APE1 to nicked apurinic/apyrimidinic sites, suggesting that APE1 prevents the promiscuous unwinding of BER intermediates. This inhibitory effect was relieved by the presence of pol . A model involving the pol -mediated hand-off of WRN protein is proposed based on these results.

Received for publication, August 20, 2004 , and in revised form, September 20, 2004.

^* This work was supported in part by the Basic Research Program Grant (R01-2003-000-00361) from the Korea Science and Engineering Foundation (to B. A.). 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: Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, MD 21224. Tel.: 410-558-8162; Fax: 410-558-8157; E-mail: vbohr{at}nih.gov.

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