Hypo-osmotic-like stress underlies general cellular defects of aneuploidy

Abstract

Aneuploidy, referring to unbalanced chromosome numbers, represents a class of genetic variation associated with cancer, birth defects and eukaryotic microbes 1 – 4 . Whereas it is known that each aneuploid chromosome stoichiometry can give rise to a distinct pattern of gene expression and phenotypic profile 4 , 5 , it has remained a fundamental question as to whether there are common cellular defects associated with aneuploidy. In this study, we designed a unique strategy that allowed for the observation of common transcriptome changes of aneuploidy by averaging out karyotype-specific dosage effects using aneuploid yeast cell populations with random and diverse chromosome stoichiometry. This analysis uncovered a common aneuploidy gene-expression (CAGE) signature suggestive of hypo-osmotic stress. Consistently, aneuploid yeast exhibited increased plasma membrane (PM) stress leading to impaired endocytosis, and this defect was also observed in aneuploid human cells. Thermodynamic modeling showed that hypo-osmotic-like stress is a general outcome of proteome imbalance caused by aneuploidy and predicted a ploidy-cell size relationship observed in yeast and aneuploid cancer cells. A genome-wide screen further uncovered a general dependency of aneuploid cells on a pathway of ubiquitin-mediated endocytic recycling of nutrient transporters. Loss of this pathway coupled with the aneuploidy-inherent endocytic defect leads to marked alteration of intracellular nutrient homeostasis.

The environmental stress response causes ribosome loss in aneuploid yeast cells

“…In the CAGE response, the genes that are upregulated in the ESR are downregulated, and those that are downregulated in the ESR are upregulated. The authors further found that the CAGE response bears similarity to a hypo-osmotic shock gene expression pattern, which was proposed to counter a decrease in cytoplasmic density observed in aneuploid cells (9,10).…”

“…A recent study (9) reported the absence of the environmental stress response (ESR) in populations of yeast cells harboring different, random aneuploid karyotypes. Instead, it was reported that these heterogeneous aneuploid yeast populations exhibit the "common aneuploidy gene-expression" (CAGE) signature.…”

“…A recent study by Tsai et al (2019;9) reported that yeast cell populations harboring heterogenous aneuploidies do not exhibit the ESR. Instead, these aneuploid populations were described to exhibit a transcriptional response, termed the "common aneuploidy gene-expression" (CAGE) response.…”

“…We report here the reanalysis of the gene expression data generated by Tsai et al (2019;9) as well as replication of their experimental approach. These analyses showed that the CAGE gene expression signature described by Tsai et al (2019;9) is an artifact caused by normalizing the gene expression of actively dividing aneuploid cells to that of euploid control cells that had grown to stationary phase. Growth into stationary phase is amongst the strongest inducers of the ESR (6).…”

“…Growth into stationary phase is amongst the strongest inducers of the ESR (6). Thus, when Tsai et al (2019;9) compared the gene expression pattern of euploid stationary phase cells to that of aneuploid cells that, due to their poor proliferation, had not yet reached stationary phase, the ESR caused by aneuploidy was obscured. We find that when exponentially growing euploid cells were used in gene expression comparisons with aneuploid cells, the CAGE signature of aneuploid cells is no longer evident.…”