Premature aging in aneuploid yeast is influenced by aneuploidy-induced defects in Ribosome Quality Control [RiboSeq]

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，但具体致病机制尚不明确，且在人类体内难以开展相关研究。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，且该现象不受遗传背景与扩增染色体类型的影响。我们发现这类缺陷部分源于非整倍体引发的核糖体质量控制（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、积聚核糖体质量控制中间体，并积累大量蛋白质聚集体。尽管非整倍体细胞的蛋白酶体功能正常，但其却表现出泛素调控异常的特征，该异常会影响细胞周期蛋白的丰度，进而破坏细胞周期阻滞过程。值得注意的是，在整倍体细胞中诱导核糖体停滞，会产生与非整倍体细胞相似的异常表型；而上调限制性核糖体质量控制亚基或泛素代谢相关蛋白的表达，则可缓解诸多非整倍体相关缺陷。本研究结果对包括唐氏综合征在内的其他非整倍体相关疾病具有重要的借鉴意义。