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Nucleic Acids Research Advance Access published online on August 22, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm500
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors

Nurten Saydam1, Radhakrishnan Kanagaraj1, Tobias Dietschy1,2,3, Patrick L. Garcia1, Javier Peña-Diaz1, Igor Shevelev2,3, Igor Stagljar2,3 and Pavel Janscak1,*

1Institute of Molecular Cancer Research of the University of Zurich, Switzerland and 2Department of Biochemistry and 3Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada

*To whom correspondence should be addressed. Tel: +41(0)44 635 3470; Fax: +41(0)44 635 3484; Email: pjanscak{at}imcr.unizh.ch

Received April 26, 2007. Revised June 7, 2007. Accepted June 7, 2007.

Werner syndrome (WS) is a severe recessive disorder characterized by premature aging, cancer predisposition and genomic instability. The gene mutated in WS encodes a bi-functional enzyme called WRN that acts as a RecQ-type DNA helicase and a 3'-5' exonuclease, but its exact role in DNA metabolism is poorly understood. Here we show that WRN physically interacts with the MSH2/MSH6 (MutS{alpha}), MSH2/MSH3 (MutSß) and MLH1/PMS2 (MutL{alpha}) heterodimers that are involved in the initiation of mismatch repair (MMR) and the rejection of homeologous recombination. MutS{alpha} and MutSß can strongly stimulate the helicase activity of WRN specifically on forked DNA structures with a 3'-single-stranded arm. The stimulatory effect of MutS{alpha} on WRN-mediated unwinding is enhanced by a G/T mismatch in the DNA duplex ahead of the fork. The MutL{alpha} protein known to bind to the MutS {alpha}–heteroduplex complexes has no effect on WRN-mediated DNA unwinding stimulated by MutS{alpha}, nor does it affect DNA unwinding by WRN alone. Our data are consistent with results of genetic experiments in yeast suggesting that MMR factors act in conjunction with a RecQ-type helicase to reject recombination between divergent sequences.

Present address: Nurten Saydam, Harvard School of Public Health, 667, Huntington Ave, Boston, USA

The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors


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