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

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.过早衰老是唐氏综合征（Down syndrome）的标志性特征，该病由人类21号染色体三体引发，但其具体成因尚不明确，且难以在人类体内开展相关研究。我们借助野生酵母构建的非整倍体（aneuploid）模型，证实染色体扩增会破坏营养诱导的细胞周期阻滞、静止态进入以及健康衰老过程，且该现象在不同遗传背景与各类扩增染色体中均会出现。我们发现，此类缺陷部分源于非整倍体诱导的核糖体质量控制（Ribosome Quality Control, RQC）功能异常。进入静止态的非整倍体细胞会出现异常的核糖体谱、积累RQC中间体，并带有更多的蛋白质聚集物。尽管非整倍体细胞的蛋白酶体（proteasome）功能正常，但它们表现出泛素（ubiquitin）调控失调的特征，这会影响细胞周期蛋白（cyclin）的丰度，进而破坏细胞周期阻滞过程。值得注意的是，在整倍体细胞（euploids）中诱导核糖体停滞，会产生类似的异常表型；而上调泛素代谢通路中限制性RQC亚基或相关蛋白的表达，则可缓解诸多非整倍体相关缺陷。我们的研究结果对包括唐氏综合征在内的其他非整倍体疾病具有重要的借鉴意义。