Article abstract
Nature Structural & Molecular Biology 16, 159 - 167 (2009)
Published online: 11 January 2009 | Corrected online: 26 January 2009 | doi:10.1038/nsmb.1544
SRS2 and SGS1 prevent chromosomal breaks and stabilize triplet repeats by restraining recombination
Alix Kerrest1,4, Ranjith P Anand2,4, Rangapriya Sundararajan2, Rodrigo Bermejo3, Giordano Liberi3, Bernard Dujon1, Catherine H Freudenreich2 & Guy-Franck Richard1
Abstract
Several molecular mechanisms have been proposed to explain trinucleotide repeat expansions. Here we show that in yeast srs2
cells, CTG repeats undergo both expansions and contractions, and they show increased chromosomal fragility. Deletion of RAD52 or RAD51 suppresses these phenotypes, suggesting that recombination triggers trinucleotide repeat instability in srs2 cells. In sgs1 cells, CTG repeats undergo contractions and increased fragility by a mechanism partially dependent on RAD52 and RAD51. Analysis of replication intermediates revealed abundant joint molecules at the CTG repeats during S phase. These molecules migrate similarly to reversed replication forks, and their presence is dependent on SRS2 and SGS1 but not RAD51. Our results suggest that Srs2 promotes fork reversal in repetitive sequences, preventing repeat instability and fragility. In the absence of Srs2 or Sgs1, DNA damage accumulates and is processed by homologous recombination, triggering repeat rearrangements.
- Institut Pasteur, Unité de Génétique Moléculaire des Levures, CNRS, URA2171, Université Pierre et Marie Curie, UFR 927, 25 rue du Dr Roux, F-75015 Paris, France.
- Department of Biology, Tufts University, Medford, Massachusetts 02155, USA.
- Instituto FIRC di Oncologia Molecolare, Via Amadello 16, 20141 Milano, Italy.
- These authors contributed equally to this work.
Correspondence to: Guy-Franck Richard1 e-mail: gfrichar@pasteur.fr
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