Aneuploidy induces premature aging in yeast due to defects in Ribosome Quality Control [RNASeqData]

Premature aging is a hallmark of Down syndrome, caused by trisomy of human chromosome 21; but the reason is unclear and difficult to study in humans. We used an aneuploid model in wild yeast to show that chromosome amplification disrupts nutrient-induced cell-cycle arrest, quiescence entry, and healthy aging, across genetic backgrounds and amplified chromosomes. We discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). Aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates. Although they have normal proteasome capacity, aneuploids show signs of ubiquitin dysregulation, which impacts cyclin abundance to disrupt arrest. Remarkably, inducing ribosome stalling in euploids produces similar aberrations, while up-regulating limiting RQC subunits or proteins in ubiquitin metabolism alleviates many of the aneuploid defects. Our results raise major implications for other aneuploidy disorders including Down syndrome. Overall design: Euploid and select aneuploid Saccharomyces cerevisiae strains (haploids with one additional copy of chromosome IV, XII, XIV, or XV). We cultured each strain in rich media, and allowed cultures to exhaust glucose and enter quiescence. Samples for RNAseq were harvested at log-phase (proliferative growth) and at days 1, 3, and 7 after start of experiment to quantify differential gene expression as euploid and aneuploid cultures enter quiescence. Each strain and timepoint was measured in biological duplicate. An equivalent amount of Schizosaccharomyces pombe was doped into each S. cer sample for downstream normalization.