The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast

Abstract

Aneuploidy produces myriad consequences in health and disease, yet models of the deleterious effects of chromosome amplification are still widely debated. To distinguish the molecular determinants of aneuploidy stress, we measured the effects of duplicating individual genes in cells with varying chromosome duplications, in wild-type cells and cells sensitized to aneuploidy by deletion of RNA-binding protein Ssd1. We identified gene duplications that are nearly neutral in wild-type euploid cells but significantly deleterious in euploids lacking SSD1 or SSD1+ aneuploid cells with different chromosome duplications. Several of the most deleterious genes are linked to translation; in contrast, duplication of other translational regulators, including eI5Fa Hyp2, benefit ssd1Δ aneuploids over controls. Using modeling of aneuploid growth defects, we propose that the deleterious effects of aneuploidy emerge from an interaction between the cumulative burden of many amplified genes on a chromosome and a subset of duplicated genes that become toxic in that context. Our results suggest that the mechanism behind their toxicity is linked to a key vulnerability in translation in aneuploid cells. These findings provide a perspective on the dual impact of individual genes and overall genomic burden, offering new avenues for understanding aneuploidy and its cellular consequences.

Premature aging in aneuploid yeast is caused in part by aneuploidy-induced defects in Ribosome Quality Control

“…Trisomy 21 in humans and chromosome amplification in sensitized W303 yeast is associated with increased protein aggregation, although the source of proteostasis stress is not known. We previously showed that wild aneuploid yeast strains do not show signs of proteostasis dysfunction unless stressed by SSD1 deletion or treated with translational inhibitor NTC 13,22 . Here we found that aging also induces protein aggregation in wild aneuploids: at 7 days of culturing, 50-70% of aneuploids with extra Chr4 or Chr12 harbored foci of protein disaggregase Hsp104, compared to ~5% of euploid cells.…”

“…Among the most intriguing on the list of 37 genes was RQC1, a component of the RQC pathway that resolves stalled ribosomes 36,37,76 . This was interesting because aneuploid strains are sensitive to translational inhibitor nourseothricin (NTC) that binds the ribosome to disrupt translation 13,22,[77][78][79] . Given that translation defects increase with cellular age [44][45][46] , these results raised the possibility that chromosome duplication induces defects in the RQC pathway.…”

“…Recent modeling work from our lab points to a defect in translational regulation in ssd1D aneuploids 22,23 . Furthermore, aneuploid yeast, especially aneuploid strains lacking SSD1, are sensitive to translational inhibitors, including nourseothricin (NTC) that binds the ribosome and disrupts translation elongation 13,22,24 . Our hypothesis is that wild S. cerevisiae isolates can handle the stress of chromosome duplication, in part through Ssd1-dependent mechanisms, but cells may be close to their buffering capacity under standard growth conditions 13 .…”

“…Ssd1 is involved in translational control and mRNA localization, and binds to several hundred transcripts encoding diverse functions [17][18][19][20][21] . Deletion of SSD1 from wild strains renders cells highly sensitive to chromosome amplification, with cells showing many of the signatures of the sensitized lab strain including proteostasis stress 13,22 . Recent modeling work from our lab points to a defect in translational regulation in ssd1D aneuploids 22,23 .…”

“…Deletion of SSD1 from wild strains renders cells highly sensitive to chromosome amplification, with cells showing many of the signatures of the sensitized lab strain including proteostasis stress 13,22 . Recent modeling work from our lab points to a defect in translational regulation in ssd1Δ aneuploids 22,23 . Furthermore, aneuploid yeast, especially aneuploid strains lacking SSD1 , are sensitive to translational inhibitors, including nourseothricin (NTC) that binds the ribosome and disrupts translation elongation 13,22,24 .…”