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Genetic or pharmacological disruption of the MSH3 Y245/K246 IDL binding pocket slows CAG repeat expansion

Rob Goold1,2, Jasmine Donaldson1,2, Florence Gidney1,2

  • 1Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.

NAR Molecular Medicine
|June 19, 2026
PubMed

Insights

Targeting the MSH3 protein

Area of Science:

  • Genetics
  • Molecular Biology
  • Neuroscience

Background:

  • Somatic expansion of CAG repeats drives Huntington's disease (HD) pathogenesis.
  • MSH3/MSH2 (Mutsβ) recognizes insertion-deletion loops (IDLs) in CAG repeats, initiating expansion.
  • MSH3 binds IDLs via a pocket formed by Y245/K246 residues.

Purpose of the Study:

  • Investigate the role of the MSH3 Y245/K246 DNA-binding motif in CAG repeat expansion.
  • Assess the therapeutic potential of targeting this MSH3 binding pocket.

Main Methods:

  • Utilized cell lines with long, unstable HTT CAG repeats.
  • Genetically disrupted the MSH3 Y245/K246 motif.
  • Employed a small molecule to pharmacologically block the MSH3 DNA-binding pocket.
  • Assessed MSH3 DNA interaction, mismatch repair (MMR) deficiency, and repeat expansion.
  • Tested the molecule in patient-derived induced pluripotent stem cell (iPSC) neurons.

Main Results:

  • Disruption of the MSH3 Y245/K246 motif reduced DNA interaction and abrogated CAG repeat expansion.
  • Genetic disruption led to MMR deficiency.
  • Pharmacological blockade of the MSH3 binding pocket reduced DNA binding and repeat expansion in cell lines.
  • The small molecule slowed CAG repeat expansion in HD patient-derived neurons.

Conclusions:

  • The MSH3 Y245/K246 motif is crucial for MSH3's role in CAG repeat expansion.
  • Targeting the MSH3 IDL binding pocket with small molecules is a viable therapeutic strategy for Huntington's disease.
  • This approach shows promise for slowing disease progression in patient-specific cells.

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