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Originally published In Press as doi:10.1074/jbc.M213103200 on March 27, 2003

J. Biol. Chem., Vol. 278, Issue 25, 22686-22695, June 20, 2003
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The Werner Syndrome Protein Stimulates DNA Polymerase {beta} Strand Displacement Synthesis via Its Helicase Activity*

Jeanine A. Harrigan {ddagger}, Patricia L. Opresko {ddagger}, Cayetano von Kobbe {ddagger}, Padmini S. Kedar §, Rajendra Prasad §, Samuel H. Wilson § and Vilhelm A. Bohr {ddagger} ¶

From the {ddagger}Laboratory of Molecular Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224 and the §Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709

Werner syndrome is a hereditary premature aging disorder characterized by genomic instability. Genetic analysis and protein interaction studies indicate that the defective gene product (WRN) may play an important role in DNA replication, recombination, and repair. DNA polymerase {beta} (pol {beta}) is a central participant in both short and long-patch base excision repair (BER) pathways, which function to process most spontaneous, alkylated, and oxidative DNA damage. We report here a physical interaction between WRN and pol {beta}, and using purified proteins reconstitute of a portion of the long-patch BER pathway to examine a potential role for WRN in this repair response. We demonstrate that WRN stimulates pol {beta} strand displacement DNA synthesis and that this stimulation is dependent on the helicase activity of WRN. In addition, a truncated WRN protein, containing primarily the helicase domain, retains helicase activity and is sufficient to mediate the stimulation of pol {beta}. The WRN helicase also unwinds a BER substrate, providing evidence that WRN plays a role in unwinding DNA repair intermediates. Based on these findings, we propose a novel mechanism by which WRN may mediate pol {beta}-directed long-patch BER.

Received for publication, December 23, 2002 , and in revised form, March 13, 2003.

* 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. Tel.: 410-558-8162; Fax: 410-558-8157; E-mail: vbohr{at}nih.gov.


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