Physical and Functional Interactions Between Werner Syndrome Helicase and Mismatch-repair Initiation Factors.
From: Institute of Molecular Cancer Research of the University of Zurich, Switzerland.
Nucleic acids research
- Publish Date: 2007
- ISSN: 1362-4962
- Volume: 35
- Issue: 17
- Pages: 5706-16
- Medium: Internet
- Language: English
- Citation (JAMA): Saydam Nurten, Kanagaraj Radhakrishnan, Dietschy Tobias, et al. Physical and Functional Interactions Between Werner Syndrome Helicase and Mismatch-repair Initiation Factors.. Nucleic Acids Res. 2007;35:5706-16
Abstract
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 (MutSalpha), MSH2/MSH3 (MutSbeta) and MLH1/PMS2 (MutLalpha) heterodimers that are involved in the initiation of mismatch repair (MMR) and the rejection of homeologous recombination. MutSalpha and MutSbeta can strongly stimulate the helicase activity of WRN specifically on forked DNA structures with a 3’-single-stranded arm. The stimulatory effect of MutSalpha on WRN-mediated unwinding is enhanced by a G/T mismatch in the DNA duplex ahead of the fork. The MutLalpha protein known to bind to the MutS alpha-heteroduplex complexes has no effect on WRN-mediated DNA unwinding stimulated by MutSalpha, 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.
Mesh Headings (Keywords): Base Pair Mismatch, Binding Sites, Cell Line, DNA, DNA Repair, DNA Repair Enzymes, DNA-Binding Proteins, Humans, MutS Homolog 2 Protein, Protein Structure, Tertiary, RecQ Helicases, Two-Hybrid System Techniques
Check for Full Text / PubMed Unique Identifier (PMID): 17715146
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