Cells express a variety of oxidant defense proteins to protect against the accumulation of reactive oxygen species. One highly conserved class of oxidant defense proteins – peroxiredoxins – play critical roles in peroxide detoxification and maintaining genome stability. For instance, the baker’s yeast peroxiredoxin Tsa1 suppresses mutations at a comparable level to certain DNA repair proteins. Initial studies in our lab have yet to determine if one of Tsa1’s three biochemical functions – peroxiredoxin, molecular chaperone, or redox signaling – causes this phenotype. However, we propose that the mutation suppression is not because of Tsa1 activity per se, but rather by altering the activity of ribonucleotide reductase (Rnr), a key enzyme in the biosynthesis of dNTPs. Both Tsa1 and Rnr undergo oxidation on cysteine residues as part of their catalytic cycle and are reduced by the thioredoxin system (Trx) to restore their catalytic activity. Thus, we propose that without Tsa1, the Trx system reduces Rnr more readily, creating an imbalance of dNTPs which lead to increased mutation rates. To test this hypothesis, we are examining how both titrating Trx away from Rnr using various pro-oxidants and suppressing Rnr directly through overexpression of specific Rnr inhibitors impacts mutation rates in Tsa1-deficient yeast. This work will shed light on the interplay between Tsa1, Rnr, and the thioredoxin system in maintaining genome stabilit

Understanding the mechanism of mutation suppression by a conserved oxidant defense protein in yeast

255th National Meeting (2018)

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