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

• Published in: The EMBO journal 2008-11, Vol.27 (21), p.2896-2906
• Main Authors: Kim, Hyun-Min, Narayanan, Vidhya, Mieczkowski, Piotr A, Petes, Thomas D, Krasilnikova, Maria M, Mirkin, Sergei M, Lobachev, Kirill S
• Format: Article
• Language: English
• Subjects: Alleles; Base Sequence; chromosomal fragility; chromosomal rearrangements; Chromosome aberrations; Chromosome Breakage; Chromosome Fragility - genetics; Chromosomes; DNA Mismatch Repair; DNA repair; DNA Replication; DNA secondary structure; Gene Rearrangement; Genes, Fungal; Genetic disorders; Genomics; mismatch repair; Models, Genetic; Molecular biology; Molecular Sequence Data; Polymorphism; Recombination, Genetic - genetics; Repetitive Sequences, Nucleic Acid - genetics; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - isolation & purification; trinucleotide repeats; Yeast; Yeasts
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2008.205

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.