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

Publication ,  Journal Article
Kim, H-M; Narayanan, V; Mieczkowski, PA; Petes, TD; Krasilnikova, MM; Mirkin, SM; Lobachev, KS
Published in: EMBO J
November 5, 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.

Duke Scholars

Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

November 5, 2008

Volume

27

Issue

21

Start / End Page

2896 / 2906

Location

England

Related Subject Headings

  • Saccharomyces cerevisiae
  • Repetitive Sequences, Nucleic Acid
  • Recombination, Genetic
  • Molecular Sequence Data
  • Models, Genetic
  • Genes, Fungal
  • Gene Rearrangement
  • Developmental Biology
  • DNA Replication
  • DNA Mismatch Repair
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Kim, H.-M., Narayanan, V., Mieczkowski, P. A., Petes, T. D., Krasilnikova, M. M., Mirkin, S. M., & Lobachev, K. S. (2008). Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair. EMBO J, 27(21), 2896–2906. https://doi.org/10.1038/emboj.2008.205
Kim, Hyun-Min, Vidhya Narayanan, Piotr A. Mieczkowski, Thomas D. Petes, Maria M. Krasilnikova, Sergei M. Mirkin, and Kirill S. Lobachev. “Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair.EMBO J 27, no. 21 (November 5, 2008): 2896–2906. https://doi.org/10.1038/emboj.2008.205.
Kim H-M, Narayanan V, Mieczkowski PA, Petes TD, Krasilnikova MM, Mirkin SM, et al. Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair. EMBO J. 2008 Nov 5;27(21):2896–906.
Kim, Hyun-Min, et al. “Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair.EMBO J, vol. 27, no. 21, Nov. 2008, pp. 2896–906. Pubmed, doi:10.1038/emboj.2008.205.
Kim H-M, Narayanan V, Mieczkowski PA, Petes TD, Krasilnikova MM, Mirkin SM, Lobachev KS. Chromosome fragility at GAA tracts in yeast depends on repeat orientation and requires mismatch repair. EMBO J. 2008 Nov 5;27(21):2896–2906.

Published In

EMBO J

DOI

EISSN

1460-2075

Publication Date

November 5, 2008

Volume

27

Issue

21

Start / End Page

2896 / 2906

Location

England

Related Subject Headings

  • Saccharomyces cerevisiae
  • Repetitive Sequences, Nucleic Acid
  • Recombination, Genetic
  • Molecular Sequence Data
  • Models, Genetic
  • Genes, Fungal
  • Gene Rearrangement
  • Developmental Biology
  • DNA Replication
  • DNA Mismatch Repair