A single amino acid substitution in MSH5 results in DNA alkylation tolerance

Gene. 2003 Oct 2;315:177-82. doi: 10.1016/s0378-1119(03)00737-6.

Abstract

DNA alkylation tolerance is a major concern in cancer chemotherapy. It has been suggested that mutations in DNA mismatch repair genes may result in alkylation tolerance. This alkylation tolerant phenotype is often manifested in cells lacking an O(6)-methylguanine DNA methyltransferase (MTase) activity. However, deletion of each mismatch repair gene in the MTase mutant of a model eukaryotic yeast does not result in alkylation tolerance. We previously isolated an alkylation tolerant mutant and mapped the mutation to MSH5. Here we present evidence that a single point mutation that results in a Y823H amino acid substitution, but not deletion, of the MSH5 gene is responsible for tolerance to killing by DNA alkylating agents. We also find that other preexisting amino acid variations may also enhance alkylation tolerance in the above mutation background. Since MSH5 encodes a protein homologous to DNA mismatch recognition proteins, mismatch repair genes are frequently mutated in cancers cells and, like mismatch repair genes, MSH5 is highly conserved from yeast to human, this observation suggests novel mechanisms of chemotherapeutic drug resistance that may occur in certain human cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / pharmacology
  • Alleles
  • Amino Acid Sequence
  • Amino Acid Substitution*
  • Cell Division / drug effects
  • Cell Division / genetics
  • Genes, Dominant / genetics
  • Methylnitronitrosoguanidine / pharmacology
  • Molecular Sequence Data
  • Point Mutation
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae Proteins / genetics*
  • Sequence Homology, Amino Acid

Substances

  • Alkylating Agents
  • MSH5 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Methylnitronitrosoguanidine