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Novel dominant mutations in Saccharomyces cerevisiae MSH6
1Ludwig Institute for Cancer Research, Department of Medicine and Cancer Center, University of California San Diego Medical School, La Jolla, California, USA.
Abstract:
Inherited mutations in the mismatch repair (MMR) genes MSH2 and MLH1 are found in most hereditary nonpolyposis colon cancer (HNPCC) patients studied. Eukaryotic MMR uses two partially redundant mispair-recognition complexes, Msh2p-Msh6p and Msh2p-Msh3p (ref.2) Inactivation of MSH2 causes high rates of accumulation of both base-substitution and frameshift mutations. Mutations in MSH6 or MSH3 cause partial defects in MMR, with inactivation of MSH6 resulting in high rates of base-substitution mutations and low rates of frameshift mutations; inactivation of MSH3 results in low rates of frameshift mutations. These different mutator phenotypes provide an explanation for the observation that MSH2 mutations are common in HNPCC families, whereas mutations in MSH3 and MSH6 are rare. We have identified novel missense mutations in Saccharomyces cerevisiae MSH6 that appear to inactivate both Msh2p-Msh6p- and Msh2p-Msh3p-dependent MMR. Our work suggests that such mutations may underlie some cases of inherited cancer susceptibility similar to those caused by MSH2 mutations.
Insights
Novel mutations in the MSH6 gene can disrupt DNA mismatch repair (MMR) pathways, similar to MSH2 gene mutations. This finding may explain some hereditary nonpolyposis colon cancer (HNPCC) cases.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Inherited mutations in mismatch repair (MMR) genes MSH2 and MLH1 are key in hereditary nonpolyposis colon cancer (HNPCC).
- Eukaryotic MMR involves Msh2p-Msh6p and Msh2p-Msh3p complexes, with distinct mutation accumulation phenotypes upon inactivation.
- MSH2 inactivation causes both base-substitution and frameshift mutations, while MSH6 and MSH3 inactivation lead to partial MMR defects.
Purpose of the Study:
- To identify novel mutations in Saccharomyces cerevisiae MSH6.
- To investigate the impact of these mutations on MSH2p-Msh6p- and MSH2p-Msh3p-dependent MMR.
- To explore the potential role of these MSH6 mutations in inherited cancer susceptibility.
Main Methods:
- Genetic analysis of Saccharomyces cerevisiae.
- Identification of novel missense mutations in the MSH6 gene.
- Functional assessment of MMR pathway defects.
Main Results:
- Novel missense mutations in yeast MSH6 were identified.
- These mutations appear to inactivate both Msh2p-Msh6p and Msh2p-Msh3p MMR complexes.
- This suggests a broader role for MSH6 mutations in MMR deficiency.
Conclusions:
- MSH6 mutations can cause significant defects in DNA mismatch repair, impacting multiple MMR complexes.
- These findings provide a potential explanation for some cases of inherited cancer susceptibility previously linked primarily to MSH2 mutations.
- Further research into MSH6 mutations is warranted for understanding HNPCC and related cancers.