The genetic basis of aneuploidy tolerance in wild yeast
James Hose,
Leah E Escalante,
Katie J Clowers,
H Auguste Dutcher,
DeElegant Robinson,
Venera Bouriakov,
Joshua J Coon,
Evgenia Shishkova,
Audrey P Gasch
Affiliations
James Hose
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States
Leah E Escalante
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States; Laboratory of Genetics, University of Wisconsin-Madison, Madison, United States
Katie J Clowers
Laboratory of Genetics, University of Wisconsin-Madison, Madison, United States
H Auguste Dutcher
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States; Laboratory of Genetics, University of Wisconsin-Madison, Madison, United States
DeElegant Robinson
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States
Venera Bouriakov
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States; Great Lakes Bioenergy Research Center, Madison, United States
Joshua J Coon
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States; Great Lakes Bioenergy Research Center, Madison, United States; Department of Biomolecular Chemistry, University of Wisconsin–Madison, Madison, United States; Department of Chemistry, University of Wisconsin–Madison, Madison, United States; Morgridge Institute for Research, Madison, United States
Evgenia Shishkova
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States; Morgridge Institute for Research, Madison, United States
Center for Genomic Science Innovation, University of Wisconsin–Madison, Madison, United States; Laboratory of Genetics, University of Wisconsin-Madison, Madison, United States; Great Lakes Bioenergy Research Center, Madison, United States
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 Saccharomyces cerevisiae 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 SSD1 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 ssd1Δ 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.
