Chromosomal instability causes sensitivity to protein folding stress and ATP depletion

Mahwish Khan, Zeeshan Shaukat, Robert Saint, Stephen Gregory

Research output: Contribution to journalArticle

4 Citations (Scopus)
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Abstract

Aneuploidy - having an unbalanced genome - is poorly tolerated at the cellular and organismal level. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift which makes these cells sensitive to internal and environmental stresses. Using Drosophila as a model, we found that protein folding stress is exacerbated by redox stress that occurs in response to ongoing changes to ploidy (chromosomal instability, CIN). We also found that if de novo nucleotide synthesis is blocked, CIN cells are dependent on a high level of lysosome function to survive. Depletion of adenosine monophosphate (AMP) synthesis enzymes led to DNA damage in CIN cells, which showed elevated activity of the DNA repair enzyme activated poly(ADP ribose) polymerase (PARP). PARP activation causes depletion of its substrate, nicotinamide adenine dinucleotide (NAD+) and subsequent loss of Adenosine Tri-Phosphate (ATP), and we found that adding ATP or nicotinamide (a precursor in the synthesis of NAD+) could rescue the observed phenotypes. These findings provide ways to interpret, target and exploit aneuploidy, which has the potential to offer tumour-specific therapies.

Original languageEnglish
Article numberbio038000
Number of pages13
JournalBiology Open
Volume7
Issue number10
DOIs
Publication statusPublished - 16 Oct 2018

Bibliographical note

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

Keywords

  • Endoplasmic reticulum
  • Protein aggregation
  • Drosophila
  • Genomic instability
  • Reactive oxygen species (ROS)

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