MSH2 ATPase domain mutation affects CTG•CAG repeat instability in transgenic mice

Stéphanie Tomé, Ian Holt, Winfried Edelmann, Glenn E. Morris, Arnold Munnich, Christopher E. Pearson, Geneviève Gourdon

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58 Scopus citations

Abstract

Myotonic dystrophy type 1 (DM1) is associated with one of the most highly unstable CTG•CAG repeat expansions. The formation of further repeat expansions in transgenic mice carrying expanded CTG•CAG tracts requires the mismatch repair (MMR) proteins MSH2 and MSH3, forming the MutSβ complex. It has been proposed that binding of MutSβ to CAG hairpins blocks its ATPase activity compromising hairpin repair, thereby causing expansions. This would suggest that binding, but not ATP hydrolysis, by MutSβ is critical for trinucleotide expansions. However, it is unknown if the MSH2 ATPase activity is dispensible for instability. To get insight into the mechanism by which MSH2 generates trinucleotide expansions, we crossed DM1 transgenic mice carrying a highly unstable >(CTG)300 repeat tract with mice carrying the G674A mutation in the MSH2 ATPase domain. This mutation impairs MSH2 ATPase activity and ablates base-base MMR, but does not affect the ability of MSH2 (associated with MSH6) to bind DNA mismatches. We found that the ATPase domain mutation of MSH2 strongly affects the formation of CTG expansions and leads instead to transmitted contractions, similar to a Msh2-null or Msh3-null deficiency. While a decrease in MSH2 protein level was observed in tissues from Msh2G674 mice, the dramatic reduction of expansions suggests that the expansion-biased trinucleotide repeat instability requires a functional MSH2 ATPase domain and probably a functional MMR system.

Original languageEnglish (US)
Article numbere1000482
JournalPLoS genetics
Volume5
Issue number5
DOIs
StatePublished - May 1 2009

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ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Tomé, S., Holt, I., Edelmann, W., Morris, G. E., Munnich, A., Pearson, C. E., & Gourdon, G. (2009). MSH2 ATPase domain mutation affects CTG•CAG repeat instability in transgenic mice. PLoS genetics, 5(5), [e1000482]. https://doi.org/10.1371/journal.pgen.1000482