Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells

Jeannine Gerhardt, Angela D. Bhalla, Jill Sergesketter Butler, James W. Puckett, Peter B. Dervan, Zev Rosenwaks, Marek Napierala, Cell Reports, Available online 14 July 2016, ISSN 2211-1247, doi:10.1016/j.celrep.2016.06.075.

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.

 Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells