Excessive rDNA Transcription Drives the Disruption in Nuclear Homeostasis during Entry into Senescence in Budding Yeast

Abstract

Summary: Budding yeast cells undergo a limited number of divisions before they enter senescence and die. Despite recent mechanistic advances, whether and how molecular events are temporally and causally linked during the transition to senescence remain elusive. Here, using real-time observation of the accumulation of extrachromosomal rDNA circles (ERCs) in single cells, we provide evidence that ERCs build up rapidly with exponential kinetics well before any physiological decline. We then show that ERCs fuel a massive increase in ribosomal RNA (rRNA) levels in the nucleolus, which do not mature into functional ribosomes. This breakdown in nucleolar coordination is followed by a loss of nuclear homeostasis, thus defining a chronology of causally related events leading to cell death. A computational analysis supports a model in which a series of age-independent processes lead to an age-dependent increase in cell mortality, hence explaining the emergence of aging in budding yeast. : The accumulation of extrachromosomal rDNA circles (ERCs) is a hallmark of aging in budding yeast. Morlot et al. show that ERCs accumulate ahead of senescence onset and fuel an excessive rDNA transcription, ultimately leading to impaired nuclear homeostasis and an irreversible cell cycle slowdown. Keywords: live cell imaging, microfluidics, yeast replicative aging, ribosome biogenesis, nucleolus, rDNA, ERCs