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, Rong Li

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)117-121
Number of pages5
JournalNature
Volume570
Issue number7759
DOIs
StatePublished - Jun 6 2019

ASJC Scopus subject areas

  • General

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    Tsai, H. J., Nelliat, A. R., Choudhury, M. I., Kucharavy, A., Bradford, W. D., Cook, M. E., Kim, J., Mair, D. B., Sun, S. X., Schatz, M. C., & Li, R. (2019). Hypo-osmotic-like stress underlies general cellular defects of aneuploidy. Nature, 570(7759), 117-121. https://doi.org/10.1038/s41586-019-1187-2