title: Loss of the thioredoxin reductase Trr1 suppresses the genomic instability of peroxiredoxin tsa1 mutants.
abstract: The absence of Tsa1, a key peroxiredoxin that scavenges H2O2 in Saccharomyces cerevisiae, causes the accumulation of a broad spectrum of mutations. Deletion of TSA1 also causes synthetic lethality in combination with mutations in RAD51 or several key genes involved in DNA double-strand break repair. In the present study, we propose that the accumulation of reactive oxygen species (ROS) is the primary cause of genome instability of tsa1Δ cells. In searching for spontaneous suppressors of synthetic lethality of tsa1Δ rad51Δ double mutants, we identified that the loss of thioredoxin reductase Trr1 rescues their viability. The trr1Δ mutant displayed a Can(R) mutation rate 5-fold lower than wild-type cells. Additional deletion of TRR1 in tsa1Δ mutant reduced substantially the Can(R) mutation rate of tsa1Δ strain (33-fold), and to a lesser extent, of rad51Δ strain (4-fold). Loss of Trr1 induced Yap1 nuclear accumulation and over-expression of a set of Yap1-regulated oxido-reductases with antioxidant properties that ultimately re-equilibrate intracellular redox environment, reducing substantially ROS-associated DNA damages. This trr1Δ -induced effect was largely thioredoxin-dependent, probably mediated by oxidized forms of thioredoxins, the primary substrates of Trr1. Thioredoxin Trx1 and Trx2 were constitutively and strongly oxidized in the absence of Trr1. In trx1Δ trx2Δ cells, Yap1 was only moderately activated; consistently, the trx1Δ trx2Δ double deletion failed to efficiently rescue the viability of tsa1Δ rad51Δ. Finally, we showed that modulation of the dNTP pool size also influences the formation of spontaneous mutation in trr1Δ and trx1Δ trx2Δ strains. We present a tentative model that helps to estimate the respective impact of ROS level and dNTP concentration in the generation of spontaneous mutations.
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ragu
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Dardalhon
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umea University, Umea, Sweden.
authors.forename: Sushma
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Ismail
authors.initials: I
authors.lastname: Iraqui
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Buhagiar-Labarchède
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Grondin
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Kienda
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Vernis
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Roland
authors.initials: R
authors.lastname: Chanet
authors.affiliation: Ludwig Institute for Cancer Research, University of California School of Medicine San Diego, La Jolla, California, United States of America.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Meng-Er
authors.initials: ME
authors.lastname: Huang
authors.affiliation: Centre National de la Recherche Scientifique, UMR3348, Orsay, France; Institut Curie, Centre de Recherche, Orsay, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Faye
mesh_terms: D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D042822:Genomic Instability; D009154:Mutation; D010544:Peroxidases / Q000235:genetics* / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C086677:YAP1 protein, S cerevisiae; D010544:Peroxidases; C496253:Tsa1 protein, S cerevisiae; D054481:Thioredoxin Reductase 1; C495151:RAD51 protein, S cerevisiae; D051135:Rad51 Recombinase