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Nucleic Acids Research 2006 34(2):745-754; doi:10.1093/nar/gkj475
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Published online 30 January 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase ß

Jeanine A. Harrigan, David M. Wilson, III, Rajendra Prasad1, Patricia L. Opresko, Gad Beck, Alfred May, Samuel H. Wilson1 and Vilhelm A. Bohr*

Laboratory of Molecular Gerontology, National Institute on Aging NIH, Baltimore, MD, USA 1Laboratory of Structural Biology, National Institute of Environmental Health Sciences, NIH Research Triangle Park, NC, USA

*To whom correspondence should be addressed. Tel: +1 410 558 8162; Fax: +1 410 558 8157; Email: vbohr{at}nih.gov

Received November 22, 2005. Revised January 11, 2006. Accepted January 11, 2006.

Genome instability is a characteristic of cancer and aging, and is a hallmark of the premature aging disorder Werner syndrome (WS). Evidence suggests that the Werner syndrome protein (WRN) contributes to the maintenance of genome integrity through its involvement in DNA repair. In particular, biochemical evidence indicates a role for WRN in base excision repair (BER). We have previously reported that WRN helicase activity stimulates DNA polymerase beta (pol ß) strand displacement synthesis in vitro. In this report we demonstrate that WRN exonuclease activity can act cooperatively with pol ß, a polymerase lacking 3'–5' proofreading activity. Furthermore, using small interference RNA technology, we demonstrate that WRN knockdown cells are hypersensitive to the alkylating agent methyl methanesulfonate, which creates DNA damage that is primarily repaired by the BER pathway. In addition, repair assays using whole cell extracts from WRN knockdown cells indicate a defect in long patch (LP) BER. These findings demonstrate that WRN plays a direct role in the repair of methylation-induced DNA damage, and suggest a role for both WRN helicase and exonuclease activities together with pol ß during LP BER.

Present addresses: Jeanine A. Harrigan, The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, UK

Patricia L. Opresko, Department of Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Pittsburgh, PA 15260, USA


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