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

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...

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Autores principales: Saydam, Nurten, Kanagaraj, Radhakrishnan, Dietschy, Tobias, Garcia, Patrick L., Peña-Diaz, Javier, Shevelev, Igor, Stagljar, Igor, Janscak, Pavel
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2034464/
https://www.ncbi.nlm.nih.gov/pubmed/17715146
http://dx.doi.org/10.1093/nar/gkm500
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author Saydam, Nurten
Kanagaraj, Radhakrishnan
Dietschy, Tobias
Garcia, Patrick L.
Peña-Diaz, Javier
Shevelev, Igor
Stagljar, Igor
Janscak, Pavel
author_facet Saydam, Nurten
Kanagaraj, Radhakrishnan
Dietschy, Tobias
Garcia, Patrick L.
Peña-Diaz, Javier
Shevelev, Igor
Stagljar, Igor
Janscak, Pavel
author_sort Saydam, Nurten
collection PubMed
description 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.
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spelling pubmed-20344642007-10-24 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 Nucleic Acids Res Nucleic Acid Enzymes 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. Oxford University Press 2007-09 2007-08-22 /pmc/articles/PMC2034464/ /pubmed/17715146 http://dx.doi.org/10.1093/nar/gkm500 Text en © 2007 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ 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.
spellingShingle Nucleic Acid Enzymes
Saydam, Nurten
Kanagaraj, Radhakrishnan
Dietschy, Tobias
Garcia, Patrick L.
Peña-Diaz, Javier
Shevelev, Igor
Stagljar, Igor
Janscak, Pavel
Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors
title Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors
title_full Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors
title_fullStr Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors
title_full_unstemmed Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors
title_short Physical and functional interactions between Werner syndrome helicase and mismatch-repair initiation factors
title_sort physical and functional interactions between werner syndrome helicase and mismatch-repair initiation factors
topic Nucleic Acid Enzymes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2034464/
https://www.ncbi.nlm.nih.gov/pubmed/17715146
http://dx.doi.org/10.1093/nar/gkm500
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