Dominant effects of an Msh6 missense mutation on DNA repair and cancer susceptibility

Cancer Cell. 2004 Aug;6(2):139-50. doi: 10.1016/j.ccr.2004.06.024.


Mutations in DNA mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC), and MMR defects are associated with a significant proportion of sporadic cancers. MMR maintains genome stability and suppresses tumor formation by preventing the accumulation of mutations and by mediating an apoptotic response to DNA damage. We describe the analysis of a dominant MSH6 missense mutation in yeast and mice that causes loss of DNA repair function while having no effect on the apoptotic response to DNA damaging agents. Our results demonstrate that MSH6 missense mutations can effectively separate the two functions, and that increased mutation rates associated with the loss of DNA repair are sufficient to drive tumorigenesis in MMR-defective tumors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cells, Cultured
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Susceptibility
  • Drug Screening Assays, Antitumor
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Mice
  • Microsatellite Repeats
  • Mutation, Missense*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phenotype
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Survival Rate


  • DNA-Binding Proteins
  • MSH6 protein, S cerevisiae
  • Msh6 protein, mouse
  • Saccharomyces cerevisiae Proteins