Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair

Hyun Min Kim, Vidhya Narayanan, Piotr A. Mieczkowski, Thomas D. Petes, Maria M. Krasilnikova, Sergei M. Mirkin, Kirill S. Lobachev

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


Expansion of triplex-forming GAA/TTC repeats in the first intron of FXN gene results in Friedreich's ataxia. Besides FXN, there are a number of other polymorphic GAA/TTC loci in the human genome where the size variations thus far have been considered to be a neutral event. Using yeast as a model system, we demonstrate that expanded GAA/TTC repeats represent a threat to eukaryotic genome integrity by triggering double-strand breaks and gross chromosomal rearrangements. The fragility potential strongly depends on the length of the tracts and orientation of the repeats relative to the replication origin, which correlates with their propensity to adopt triplex structure and to block replication progression. We show that fragility is mediated by mismatch repair machinery and requires the MutSβ and endonuclease activity of MutLα. We suggest that the mechanism of GAA/TTC-induced chromosomal aberrations defined in yeast can also operate in human carriers with expanded tracts.

Original languageEnglish (US)
Pages (from-to)2896-2906
Number of pages11
JournalEMBO Journal
Issue number21
StatePublished - Nov 5 2008

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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