Large-Scale Expansions of Friedreich's Ataxia GAA Repeats in Yeast

Alexander A. Shishkin, Irina Voineagu, Robert Matera, Nicole Cherng, Brook T. Chernet, Maria M. Krasilnikova, Vidhya Narayanan, Kirill S. Lobachev, Sergei M. Mirkin

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92 Scopus citations

Abstract

Large-scale expansions of DNA repeats are implicated in numerous hereditary disorders in humans. We describe a yeast experimental system to analyze large-scale expansions of triplet GAA repeats responsible for the human disease Friedreich's ataxia. When GAA repeats were placed into an intron of the chimeric URA3 gene, their expansions caused gene inactivation, which was detected on the selective media. We found that the rates of expansions of GAA repeats increased exponentially with their lengths. These rates were only mildly dependent on the repeat's orientation within the replicon, whereas the repeat-mediated replication fork stalling was exquisitely orientation dependent. Expansion rates were significantly elevated upon inactivation of the replication fork stabilizers, Tof1 and Csm3, but decreased in the knockouts of postreplication DNA repair proteins, Rad6 and Rad5, and the DNA helicase Sgs1. We propose a model for large-scale repeat expansions based on template switching during replication fork progression through repetitive DNA.

Original languageEnglish (US)
Pages (from-to)82-92
Number of pages11
JournalMolecular cell
Volume35
Issue number1
DOIs
StatePublished - Jul 10 2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Shishkin, A. A., Voineagu, I., Matera, R., Cherng, N., Chernet, B. T., Krasilnikova, M. M., Narayanan, V., Lobachev, K. S., & Mirkin, S. M. (2009). Large-Scale Expansions of Friedreich's Ataxia GAA Repeats in Yeast. Molecular cell, 35(1), 82-92. https://doi.org/10.1016/j.molcel.2009.06.017