Large expansion of CTG•CAG repeats is exacerbated by MutSβ in human cells

Sci Rep. 2015 Jun 5;5:11020. doi: 10.1038/srep11020.


Trinucleotide repeat expansion disorders (TRED) are caused by genomic expansions of trinucleotide repeats, such as CTG and CAG. These expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have demonstrated the involvement of DNA repair proteins in repeat instability, although the key factors affecting large repeat expansion and contraction are unclear. Here we investigated these factors in a human cell model harboring 800 CTG•CAG repeats by individually knocking down various DNA repair proteins using short interfering RNA. Knockdown of MSH2 and MSH3, which form the MutSβ heterodimer and function in mismatch repair, suppressed large repeat expansions, whereas knockdown of MSH6, which forms the MutSα heterodimer with MSH2, promoted large expansions exceeding 200 repeats by compensatory increases in MSH3 and the MutSβ complex. Knockdown of topoisomerase 1 (TOP1) and TDP1, which are involved in single-strand break repair, enhanced large repeat contractions. Furthermore, knockdown of senataxin, an RNA/DNA helicase which affects DNA:RNA hybrid formation and transcription-coupled nucleotide excision repair, exacerbated repeat instability in both directions. These results indicate that DNA repair factors, such as MutSβ play important roles in large repeat expansion and contraction, and can be an excellent therapeutic target for TRED.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • DNA Helicases
  • DNA Topoisomerases, Type I / chemistry
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dimerization
  • Genomic Instability
  • Humans
  • Multifunctional Enzymes
  • MutS Homolog 2 Protein / antagonists & inhibitors
  • MutS Homolog 2 Protein / genetics
  • MutS Homolog 2 Protein / metabolism*
  • MutS Homolog 3 Protein
  • Myotonic Dystrophy / genetics
  • Myotonic Dystrophy / pathology
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism
  • RNA Helicases / antagonists & inhibitors
  • RNA Helicases / genetics
  • RNA Helicases / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Trinucleotide Repeat Expansion / genetics*


  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MSH3 protein, human
  • Multifunctional Enzymes
  • MutS Homolog 3 Protein
  • RNA, Small Interfering
  • Phosphoric Diester Hydrolases
  • TDP1 protein, human
  • SETX protein, human
  • MSH2 protein, human
  • MutS Homolog 2 Protein
  • DNA Helicases
  • RNA Helicases
  • DNA Topoisomerases, Type I
  • TOP1 protein, human