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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Kim, H-M; Narayanan, V; Mieczkowski, PA; Petes, TD; Krasilnikova, MM; Mirkin, SM; Lobachev, KS

Published Date

  • November 5, 2008

Published In

Volume / Issue

  • 27 / 21

Start / End Page

  • 2896 - 2906

PubMed ID

  • 18833189

Pubmed Central ID

  • PMC2580784

Electronic International Standard Serial Number (EISSN)

  • 1460-2075

Digital Object Identifier (DOI)

  • 10.1038/emboj.2008.205


  • eng

Conference Location

  • England