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

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Myotonic dystrophy type 1 (DM1) is characterized by highly unstable CTG*CAG repeat expansions.
• The mismatch repair (MMR) complex MutSbeta, composed of MSH2 and MSH3, is crucial for repeat expansions in DM1 models.
• A hypothesis suggests MutSbeta binding to CAG hairpins, rather than ATP hydrolysis, drives expansions.

Purpose of the Study:

• To investigate the role of MSH2 ATPase activity in trinucleotide repeat expansions in DM1.
• To determine if MSH2's ATP hydrolysis function is essential for CTG repeat instability.

Main Methods:

• Generated transgenic DM1 mice with an expanded CTG repeat tract.
• Crossed these mice with mice carrying a G674A mutation in the MSH2 ATPase domain, impairing its activity.
• Analyzed CTG repeat length changes and MSH2 protein levels in affected tissues.

Main Results:

• The MSH2 ATPase domain mutation significantly reduced CTG repeat expansions.
• Instead of expansions, these mice exhibited repeat contractions, similar to Msh2-null or Msh3-null mice.
• A decrease in MSH2 protein levels was noted in Msh2(G674) mice.

Conclusions:

• Functional MSH2 ATPase activity is required for expansion-biased trinucleotide repeat instability in DM1.
• The MMR system likely plays a critical role in repeat expansions, dependent on MSH2's functional ATPase domain.
• These findings challenge the hypothesis that mere binding, without ATP hydrolysis, drives expansions.