Abstract
Asymmetric division in Saccharomyces cerevisiae generates an aging mother cell and a rejuvenated daughter cell. The accumulation of Extrachromosomal rDNA Circles (ERCs) and their specific retention in mothers have been hypothesized to be responsible for replicative aging. However, it remains unclear by which molecular mechanisms ERCs would trigger the cell cycle slow-down occurring during replicative aging and leading to cell death. In this study, we show that ERCs accumulation is initiated within the 5 divisions preceding the onset of cell cycle decline. The generation of ERCs is also concomitant with a nucleolar stress characterized by an up-regulation of RNA polymerase I activity and an accumulation of pre-rRNAs in the nucleolus which do not lead neither to a higher production of ribosomes, nor to an increased growth rate. We further demonstrate that this nucleolar stress observed in old mothers is not inherited by daughters, which recover basal RNA polymerase I activity and normal cell cycle durations following an asymmetrical nuclear division. In the long-lived mutant fob1∆, we identified a sub-population, with a further extended longevity, which does not present neither a nucleolar stress nor a cell cycle slow down prior to cell death. Altogether, these findings support a causal role for the nucleolar stress in entering cellular senescence.