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

Research output: Contribution to journalLetter

Authors

  • 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

Colleges, School and Institutes

External organisations

  • Center for Cell Dynamics
  • Johns Hopkins University
  • Stowers Institute for Medical Research
  • Johns Hopkins University

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.

Details

Original languageEnglish
Pages (from-to)117-121
Number of pages5
JournalNature
Volume570
Issue number7759
Early online date18 May 2019
Publication statusPublished - 6 Jun 2019

ASJC Scopus subject areas