PDF(Pubmed)
Abstract：
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). Compared to euploids, 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 provide implications for other aneuploidy disorders including Down syndrome.
摘要：
过早衰老是唐氏综合症的标志,由人类21号染色体三体性引起，但原因尚不清楚，难以在人类中研究。我们在野生酵母中使用非整倍体模型来显示染色体扩增破坏营养诱导的细胞周期停滞，静止进入,和健康的衰老，跨越遗传背景和扩增染色体。我们发现这些缺陷部分是由于核糖体质量控制（RQC）中的非整倍性诱导的功能障碍。与整倍体相比，进入静止的非整倍体显示异常核糖体谱，积累RQC中间体，并增加了蛋白质聚集体的负荷。虽然它们有正常的蛋白酶体能力，非整倍体显示泛素失调的迹象，影响细胞周期蛋白的丰度以扰乱逮捕。值得注意的是,在整倍体中诱导核糖体停滞会产生类似的畸变，而上调泛素代谢中的限制性RQC亚基或蛋白质可减轻许多非整倍体缺陷。我们的结果为包括唐氏综合征在内的其他非整倍体疾病提供了启示。
