Senescence in yeast is associated with chromosome XII cleavage rather than ribosomal DNA circle accumulation

Abstract

The massive accumulation of extrachromosomal ribosomal DNA circles (ERCs) in yeast mother cells has been long cited as the primary driver of replicative ageing. ERCs arise through ribosomal DNA (rDNA) recombination and a wealth of genetic data connects rDNA instability to shortened lifespan and other ageing pathologies. However, we understand little about the molecular effects of ERC accumulation. Here we analysed the widespread disruption of gene expression that accompanies yeast ageing, and unexpectedly found this to be independent of ERCs. Furthermore, we found no evidence of gene expression differences in the presence of ERCs that might indicate stress responses or metabolic feedback. Accumulation of Tom70-GFP, a marker for the onset of cell division defects at the Senescence Entry Point (SEP), also correlated poorly to ERC abundance but displayed a transcriptomic signature separable from age. This signature is dominated by copy number amplification of a region of chromosome XII between the rDNA and the telomere (ChrXIIr) which arises in aged cells due to rDNA instability, but through a different mechanism to ERCs. Our findings implicate ChrXIIr, rather than ERCs, as the primary driver of senescence during budding yeast ageing.