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

Hung-Ji Tsai, Anjali R. Nelliat, Mohammad Ikbal Choudhury, Andrei Kucharavy, William D. Bradford, Malcolm E. Cook, Jisoo Kim, Devin B. Mair, Sean X. Sun, Michael C. Schatz and Rong Li ()
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Hung-Ji Tsai: Johns Hopkins University School of Medicine
Anjali R. Nelliat: Johns Hopkins University School of Medicine
Mohammad Ikbal Choudhury: Johns Hopkins University
Andrei Kucharavy: Johns Hopkins University School of Medicine
William D. Bradford: Stowers Institute for Medical Research
Malcolm E. Cook: Stowers Institute for Medical Research
Jisoo Kim: Johns Hopkins University School of Medicine
Devin B. Mair: Johns Hopkins University School of Medicine
Sean X. Sun: Johns Hopkins University
Michael C. Schatz: Johns Hopkins University
Rong Li: Johns Hopkins University School of Medicine

Nature, 2019, vol. 570, issue 7759, 117-121

Abstract: Abstract Aneuploidy, which refers to unbalanced chromosome numbers, represents a class of genetic variation that is associated with cancer, birth defects and eukaryotic micro-organisms1–4. Whereas it is known that each aneuploid chromosome stoichiometry can give rise to a distinct pattern of gene expression and phenotypic profile4,5, it remains a fundamental question as to whether there are common cellular defects that are associated with aneuploidy. Here we show the existence in budding yeast of a common aneuploidy gene-expression signature that is suggestive of hypo-osmotic stress, using a strategy that enables the observation of common transcriptome changes of aneuploidy by averaging out karyotype-specific dosage effects in aneuploid yeast-cell populations with random and diverse chromosome stoichiometry. Consistently, aneuploid yeast exhibited increased plasma-membrane stress that led to impaired endocytosis, and this defect was also observed in aneuploid human cells. Thermodynamic modelling showed that hypo-osmotic-like stress is a general outcome of the proteome imbalance that is caused by aneuploidy, and also predicted a relationship between ploidy and cell size that was observed in yeast and aneuploid cancer cells. A genome-wide screen 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 endocytic defect inherent to aneuploidy, leads to a marked alteration of intracellular nutrient homeostasis.

Date: 2019
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DOI: 10.1038/s41586-019-1187-2

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