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

Research output: Contribution to journalArticle

57 Citations (Scopus)

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 2009

Fingerprint

Transgenic Mice
repair
adenosinetriphosphatase
Adenosine Triphosphatases
mutation
genetically modified organisms
Mutation
DNA Mismatch Repair
mice
protein
base pair mismatch
Trinucleotide Repeat Expansion
contraction
hydrolysis
Myotonic Dystrophy
DNA
Proteins
Hydrolysis
proteins
Adenosine Triphosphate

ASJC Scopus subject areas

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

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

MSH2 ATPase domain mutation affects CTG•CAG repeat instability in transgenic mice. / Tomé, Stéphanie; Holt, Ian; Edelmann, Winfried; Morris, Glenn E.; Munnich, Arnold; Pearson, Christopher E.; Gourdon, Geneviève.

In: PLoS Genetics, Vol. 5, No. 5, e1000482, 05.2009.

Research output: Contribution to journalArticle

Tomé, S, Holt, I, Edelmann, W, Morris, GE, Munnich, A, Pearson, CE & Gourdon, G 2009, 'MSH2 ATPase domain mutation affects CTG•CAG repeat instability in transgenic mice', PLoS Genetics, vol. 5, no. 5, e1000482. https://doi.org/10.1371/journal.pgen.1000482
Tomé, Stéphanie ; Holt, Ian ; Edelmann, Winfried ; Morris, Glenn E. ; Munnich, Arnold ; Pearson, Christopher E. ; Gourdon, Geneviève. / MSH2 ATPase domain mutation affects CTG•CAG repeat instability in transgenic mice. In: PLoS Genetics. 2009 ; Vol. 5, No. 5.
@article{1611700a27dd4371a98b463f5354a68d,
title = "MSH2 ATPase domain mutation affects CTG•CAG repeat instability in transgenic mice",
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.",
author = "St{\'e}phanie Tom{\'e} and Ian Holt and Winfried Edelmann and Morris, {Glenn E.} and Arnold Munnich and Pearson, {Christopher E.} and Genevi{\`e}ve Gourdon",
year = "2009",
month = "5",
doi = "10.1371/journal.pgen.1000482",
language = "English (US)",
volume = "5",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - MSH2 ATPase domain mutation affects CTG•CAG repeat instability in transgenic mice

AU - Tomé, Stéphanie

AU - Holt, Ian

AU - Edelmann, Winfried

AU - Morris, Glenn E.

AU - Munnich, Arnold

AU - Pearson, Christopher E.

AU - Gourdon, Geneviève

PY - 2009/5

Y1 - 2009/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=67149083322&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67149083322&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1000482

DO - 10.1371/journal.pgen.1000482

M3 - Article

C2 - 19436705

AN - SCOPUS:67149083322

VL - 5

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 5

M1 - e1000482

ER -