Mutator phenotype due to loss of heterozygosity in diploid yeast strains with mutations in MSH2 and MLH1

Karin Drotschmann, Polina V. Shcherbakova, Thomas A. Kunkel

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Mutations in mismatch repair (MMR) genes predispose humans to cancer. Particularly prevalent are frameshift and point mutations in MSH2 and MLH1, two genes whose products are required for the early steps in MMR. In normal tissues of persons predisposed to hereditary non-polyposis colon cancer (HNPCC), these mutations are usually present in only one allele. In tumor cells of these patients, the second, wild type allele is typically found to be deleted or inactivated by point mutation. This suggests that loss of heterozygosity (LOH) results in a strong mutator phenotype that could eventually lead to the onset of disease. Here we demonstrate that diploid yeast strains that are heterozygous for MSH2 and MLH1 alleles have an elevated mutation rate. We further show that this effect results not from saturation of the MMR capacity of all cells in the population, but rather from loss of the wild type allele in a subpopulation of heterozygous cells. These results have implications for understanding the mechanisms of carcinogenesis in humans. Copyright (C) 2000 Elsevier Science Ireland Ltd.

Original languageEnglish (US)
Pages (from-to)239-244
Number of pages6
JournalToxicology Letters
Volume112-113
DOIs
StatePublished - Mar 15 2000
Externally publishedYes

Keywords

  • Colon cancer
  • MLH1
  • MSH2
  • Mismatch repair

ASJC Scopus subject areas

  • Toxicology

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