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Nucleic Acids Research, 2001, Vol. 29, No. 9 1926-1934
© 2001 Oxford University Press

A functional interaction of Ku with Werner exonuclease facilitates digestion of damaged DNA

David K. Orren1,3, Amrita Machwe2, Parimal Karmakar2, Jason Piotrowski2, Marcus P. Cooper2,3 and Vilhelm A. Bohr2,*

1Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA, 2Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA and 3Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Werner syndrome (WS) is a premature aging disorder where the affected individuals appear much older than their chronological age. The single gene that is defective in WS encodes a protein (WRN) that has ATPase, helicase and 3'->5' exonuclease activities. Our laboratory has recently uncovered a physical and functional interaction between WRN and the Ku heterodimer complex that functions in double-strand break repair and V(D)J recombination. Importantly, Ku specifically stimulates the exonuclease activity of WRN. We now report that Ku enables the Werner exonuclease to digest through regions of DNA containing 8-oxoadenine and 8-oxoguanine modifications, lesions that have previously been shown to block the exonuclease activity of WRN alone. These results indicate that Ku significantly alters the exonuclease function of WRN and suggest that the two proteins function concomitantly in a DNA damage processing pathway. In support of this notion we also observed co-localization of WRN and Ku, particularly after DNA damaging treatments.

* To whom correspondence should be addressed. Tel: +1 410 558 8162; Fax: +1 410 558 8157; Email: vbohr{at}nih.gov The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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