The peroxiredoxin Tsa1 extends the lifespan of budding yeast by maintaining the stability of the ribosomal RNA gene cluster

Tsa1 is a major budding yeast peroxiredoxin that also has nonperoxidase functions. Here we demonstrate that Tsa1 is required for stabilizing the ribosomal RNA gene (rDNA) cluster. Tsa1 deficiency led to lower replication initiation and an elevated recombination frequency in the rDNA. However, the absence of Tsa1 did not affect Fob1-dependent replication fork arrest at the replication fork barrier (RFB) site, indicating that forks at this site are arrested stably. Tsa1 deficiency did not affect the frequency of DNA double-strand breaks (DSBs) but enhanced transcription from the regulatory promoter E-pro toward the RFB. Because transcription from E-pro inhibits cohesin association and DSB end resection, elevated transcription may cause rDNA instability. We showed that the shortened lifespan and rDNA instability in the tsa1 Δ mutant were largely suppressed by the fob1 mutation. Therefore, Tsa1-mediated rDNA stabilization in response to replication fork arrest is important for prolonging lifespan. The tsa1 Δ mutant accumulated single-strand breaks in the rDNA in a Fob1-independent manner. Taken together, these findings suggest that Tsa1 plays a crucial role in maintaining rDNA stability in both Fob1-dependent and Fob1-independent manners and contributes to lifespan extension.