NDLI: Chromosomal instability causes sensitivity to protein folding stress and ATP depletion

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Chromosomal instability causes sensitivity to protein folding stress and ATP depletion

Content Provider	Semantic Scholar
Author	Khan, Mahwish Shaukat, Zeeshan Saint, Robert Gregory, Stephen L.
Copyright Year	2018
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.
Starting Page	29
Ending Page	43
Page Count	15
File Format	PDF HTM / HTML
PubMed reference number	30327366v1
Alternate Webpage(s)	https://doi.org/10.1242/bio.038000
DOI	10.1242/bio.038000
Journal	Biology open
Volume Number	7
Language	English
Access Restriction	Open
Subject Keyword	Adenosine Monophosphate Aneuploidy Cervical Intraepithelial Neoplasia Chromosomal Instability Chromosomal Proteins, Non-Histone Cyclic AMP DNA Damage Dinucleoside Phosphates Neoplasms Niacin Niacinamide Nicotinamide adenine dinucleotide (NAD) Nucleotides Organism Phenotype Ribose Therapeutic procedure protein folding
Content Type	Text
Resource Type	Article

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