The genetic basis of aneuploidy tolerance in wild yeast.

Abstract

Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi - what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of <i>Saccharomyces cerevisiae</i> tolerate chromosome amplification while laboratory strains used as a model for aneuploid syndromes do not. Here, we mapped the genetic basis to Ssd1, an RNA-binding translational regulator that is functional in wild aneuploids but defective in laboratory strain W303. Loss of <i>SSD1</i> recapitulates myriad aneuploidy signatures previously taken as eukaryotic responses. We show that aneuploidy tolerance is enabled via a role for Ssd1 in mitochondrial physiology, including binding and regulating nuclear-encoded mitochondrial mRNAs, coupled with a role in mitigating proteostasis stress. Recapitulating <i>ssd1Δ</i> defects with combinatorial drug treatment selectively blocked proliferation of wild-type aneuploids compared to euploids. Our work adds to elegant studies in the sensitized laboratory strain to present a mechanistic understanding of eukaryotic aneuploidy tolerance.