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

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

In: Nucleic Acids Research, 2007, vol. 35, no. 17, p. 5706-5716

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    Title
    • Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors
    Author
    • Saydam, Nurten. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    • Kanagaraj, Radhakrishnan. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    • Dietschy, Tobias. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    • Garcia, Patrick L.. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    • Peña-Diaz, Javier. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    • Shevelev, Igor. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    • Stagljar, Igor. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    • Janscak, Pavel. Institute of Molecular Cancer Research of the University of Zurich, Switzerland, Department of Biochemistry and Department of Medical Genetics and Microbiology, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Canada
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Nucleic Acids Research, 2007, vol. 35, no. 17, p. 5706-5716. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:299398
    Summary
    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