Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich's Ataxia Cells Academic Article uri icon


MeSH Major

  • DNA Replication
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome
  • Promoter Regions, Genetic
  • Replication Origin


  • Friedreich's ataxia (FRDA) is caused by the expansion of GAA repeats located in the Frataxin (FXN) gene. The GAA repeats continue to expand in FRDA patients, aggravating symptoms and contributing to┬ádisease progression. The mechanism leading to repeat expansion and decreased FXN transcription remains unclear. Using single-molecule analysis of replicated DNA, we detected that expanded GAA repeats present a substantial obstacle for the replication machinery at the FXN locus in FRDA cells. Furthermore, aberrant origin activation and lack of a proper stress response to rescue the stalled forks in FRDA cells cause an increase in 3'-5' progressing forks, which could enhance repeat expansion and hinder FXN transcription by head-on collision with RNA polymerases. Treatment of FRDA cells with GAA-specific polyamides rescues DNA replication fork stalling and alleviates expansion of the GAA repeats, implicating DNA triplexes as a replication impediment and suggesting that fork stalling might be a therapeutic target for FRDA.

publication date

  • August 2, 2016



  • Academic Article



  • eng

PubMed Central ID

  • PMC5028224

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2016.06.075

PubMed ID

  • 27425605

Additional Document Info

start page

  • 1218

end page

  • 27


  • 16


  • 5