Loss of the thioredoxin reductase Trr1 suppresses the genomic instability of peroxiredoxin tsa1 mutants

• 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 tsa1 Delta cells. In searching for spontaneous suppressors of synthetic lethality of tsa1 Delta rad51 Delta double mutants, we identified that the loss of thioredoxin reductase Trr1 rescues their viability. The trr1 Delta mutant displayed a Can(R) mutation rate 5-fold lower than wild-type cells. Additional deletion of TRR1 in tsa1 Delta mutant reduced substantially the Can(R) mutation rate of tsa1 Delta strain (33-fold), and to a lesser extent, of rad51 Delta strain (4-fold). Loss of Trr1 induced Yap1 nuclear accumulation and over-expression of a set of Yap1-regulated oxidoreductases with antioxidant properties that ultimately re-equilibrate intracellular redox environment, reducing substantially ROS-associated DNA damages. This trr1 Delta -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 trx1 Delta trx2 Delta cells, Yap1 was only moderately activated; consistently, the trx1 Delta trx2 Delta double deletion failed to efficiently rescue the viability of tsa1 Delta rad51 Delta. Finally, we showed that modulation of the dNTP pool size also influences the formation of spontaneous mutation in trr1 Delta and trx1 Delta trx2 Delta 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.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biofysik (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biophysics (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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