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Novel dominant mutations in Saccharomyces cerevisiae MSH6

Nature Genetics volume 24, pages 53–56 (2000)Cite this article

Abstract

Inherited mutations in the mismatch repair (MMR) genes MSH2 and MLH1 are found in most hereditary nonpolyposis colon cancer (HNPCC) patients studied1. 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 rare1,3,5. 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.

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Figure 1: Schematic of the Msh6 protein showing the location of known motifs.
Figure 2: Gel shifts with cell extracts overexpressing Msh2p and Msh6p and GT heteroduplex.
Figure 3: Models for the interactions between MMR proteins and mispaired bases in wild-type S. cerevisiae strains and strains containing different msh6 mutations.

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Acknowledgements

We thank the Ludwig Institute for Cancer Reseach Core Sequencing Facility (J. Weger and J. Sansone) for all the sequencing done for this project; P. Hunt for assistance with fluctutation analysis of the site-directed mutants; E. Alani for Msh6p polyclonal antibody; and members of the Kolodner laboratory for comments on the manuscript. This work was supported by NIH grant GM50006.

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  1. Department of Medicine and Cancer Center, Ludwig Institute for Cancer Research, University of California San Diego Medical School, La Jolla, California, USA

    Ruchira Das Gupta & Richard D. Kolodner

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  1. Ruchira Das Gupta
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  2. Richard D. Kolodner
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Correspondence to Richard D. Kolodner.

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Das Gupta, R., Kolodner, R. Novel dominant mutations in Saccharomyces cerevisiae MSH6. Nat Genet 24, 53–56 (2000). https://doi.org/10.1038/71684

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