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

Nurten Saydam, Radhakrishnan Kanagaraj, Tobias Dietschy, Patrick I. Garcia, Javier Peña-Diaz, Igor Shevelev, Igor Stagljar, Pavel Janscak

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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 (MutSα), MSH2/MSH3 (MutSβ) and MLH1/PMS2 (MutLα) heterodimers that are involved in the initiation of mismatch repair (MMR) and the rejection of homeologous recombination. MutSα and MutSβ can strongly stimulate the helicase activity of WRN specifically on forked DNA structures with a 3′-single-stranded arm. The stimulatory effect of MutSα on WRN-mediated unwinding is enhanced by a G/T mismatch in the DNA duplex ahead of the fork. The MutLα protein known to bind to the MutS α-heteroduplex complexes has no effect on WRN-mediated DNA unwinding stimulated by MutSα, 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.

Original languageEnglish (US)
Pages (from-to)5706-5716
Number of pages11
JournalNucleic acids research
Issue number17
StatePublished - Sep 2007

Bibliographical note

Funding Information:
We thank Renjie Jiao for the construction of pACT2-WRN plasmid used in YTH assay, Peter Cejka for purified E. coli MutS protein and Lene Rasmussen for the plasmid pLJR105. We are also grateful to Josef Jiricny, Stefano Ferrari and David Lauterbach for comments on the manuscript. This work was supported by the Sassella and the Swiss National Science Foundations (Marie Heim-Vögtlin Grant Nr. PMPDA-102451 to N.S.). Funding to pay the Open Access publication charges for this article was provided by the Swiss National Science Foundation.


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