Defects in the NuA4 acetyltransferase complex increase stability of the ribosomal RNA gene and extend replicative lifespan

Genome instability is a cause of cellular senescence. The ribosomal RNA gene repeat (rDNA) is one of the most unstable regions in the genome and its instability is proposed to be a major inducer of cellular senescence and restricted lifespan. We previously conducted a genome-wide screen using a budding yeast deletion library to identify mutants that exhibit a change in the stability of the rDNA region, compared to the wild-type. To investigate the correlation between rDNA stability and lifespan, we examined deletion mutants with very stable rDNA and found that deletion of EAF3, encoding a component of the NuA4 histone acetyltransferase complex, reproducibly resulted in increased stabilization of the rDNA. In the absence of Eaf3, and of other subunits of the NuA4 complex, we observed lower levels of extrachromosomal rDNA circles that are produced by recombination in the rDNA and are thus an indicator of rDNA instability. The replicative lifespan in the eaf3 mutant was extended by -30%, compared to the wild-type strain. Our findings provide evidence that rDNA stability is correlated with extended replicative lifespan. The eaf3 mutation possibly affects the non -coding transcription in rDNA that regulates rDNA recombination through cohesin dissociation.