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Nature. 2019 Jun;570(7759):117-121. doi: 10.1038/s41586-019-1187-2. Epub 2019 May 8.

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

Author information

1
Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
3
Department of Mechanical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
4
Stowers Institute for Medical Research, Kansas City, MO, USA.
5
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
Department of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
7
Center for Cell Dynamics, Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. rong@jhu.edu.
8
Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA. rong@jhu.edu.

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.

PMID:
31068692
DOI:
10.1038/s41586-019-1187-2

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