SRS2 and SGS1 prevent chromosomal breaks and stabilize triplet repeats by restraining recombination.
Several molecular mechanisms have been proposed to explain trinucleotide repeat expansions. Here we show that in yeast srs2Delta 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 srs2Delta cells. In sgs1Delta 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.
Kerrest
Alix
A
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.
Anand
Ranjith P
RP
Sundararajan
Rangapriya
R
Bermejo
Rodrigo
R
Liberi
Giordano
G
Dujon
Bernard
B
Freudenreich
Catherine H
CH
Richard
Guy-Franck
GF
D019457:Chromosome Breakage; D002873:Chromosome Fragility; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D017353:Gene Deletion; D006801:Humans; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D051721:Rad52 DNA Repair and Recombination Protein / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D018911:Trinucleotide Repeats
C497197:RAD52 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; C061376:SRS2 protein, S cerevisiae; D051135:Rad51 Recombinase; C090472:SGS1 protein, S cerevisiae; D004265:DNA Helicases; D053484:RecQ Helicases