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  • The EMBO Journal (2008) 27, 2896 - 2906
  • doi:10.1038/emboj.2008.205

Published online: 2 October 2008

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

Hyun-Min Kim1, Vidhya Narayanan1, Piotr A Mieczkowski2,a, Thomas D Petes2, Maria M Krasilnikova3, Sergei M Mirkin4 and Kirill S Lobachev1

  1. School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
  2. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA
  3. Department of Biochemistry and Molecular Biology, Penn State University, University Park, PA, USA
  4. Department of Biology, Tufts University, Medford, MA, USA

Correspondence to:

Kirill S Lobachev, School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 310 Ferst Drive, Cherry Emerson Building, Atlanta, GA 30332, USA. Tel.: +1 404 385 6197; Fax: +1 404 894 0519; E-mail: kirill.lobachev@biology.gatech.edu

aPresent address: Department of Genetics and the Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

Received 29 July 2008; Accepted 15 September 2008

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 MutSbeta and endonuclease activity of MutLalpha. We suggest that the mechanism of GAA/TTC-induced chromosomal aberrations defined in yeast can also operate in human carriers with expanded tracts.

  • Keywords:

    • chromosomal fragility,
    • chromosomal rearrangements,
    • DNA secondary structure,
    • mismatch repair,
    • trinucleotide repeats