The Genetic Basis of Aneuploidy Tolerance in Wild Yeast

Aneuploidy, in which cells carry an abnormal chromosome count, is detrimental during development yet common in human cancers; why cells differ in tolerance remains unclear. We mapped the genetic basis of aneuploidy tolerance in wild Saccharomyces cerevisiae versus the sensitive lab strain to Ssd1, an RNA-binding protein involved in translation whose loss recapitulates aneuploidy signatures in laboratory yeast. We find Ssd1 localizes to mitochondria, influences localization of nuclear-encoded mitochondrial mRNAs and/or abundance of the encoded proteins, influences mitochondrial function, and minimizes protein aggregates upon chromosome amplification. Recapitulating ssd1D defects with combinatorial drug treatment selectively targets wild-type aneuploids in multiple strains, suggesting therapeutic approaches. Our work adds to elegant studies done in the sensitized laboratory strain to present a mechanistic understanding of aneuploidy tolerance in eukaryotes.非整倍性（aneuploidy）指细胞携带异常染色体数的状态，其在发育过程中具有有害影响，却在人类癌症中十分常见；目前细胞间非整倍性耐受性存在差异的原因仍不明确。我们将野生型酿酒酵母（Saccharomyces cerevisiae）与敏感实验室菌株的非整倍性耐受性遗传基础定位至Ssd1——一种参与翻译过程的RNA结合蛋白（RNA-binding protein），该蛋白的缺失可在实验室酵母中重现非整倍性特征。我们发现，Ssd1定位于线粒体，可影响核编码线粒体mRNA的定位及/或其所编码蛋白的丰度，调控线粒体功能，并在染色体扩增时减少蛋白质聚集。通过联合药物治疗重现ssd1基因缺失的缺陷表型，可在多种菌株中选择性靶向野生型非整倍体细胞，这为开发相关治疗策略提供了思路。本研究作为此前在致敏实验室菌株中开展的精巧研究的补充，为真核生物的非整倍性耐受性提供了机制层面的理解。