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Chromosomal instability causes sensitivity to polyamines and one-carbon metabolism

ABSTRACT: Chromosomal instability causes sensitivity to polyamines and one-carbon metabolism

PROVIDER: PRJNA966989 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24422500_1.fastq.gz	Fastqsanger.gz
	SRR24422500_2.fastq.gz	Fastqsanger.gz
	SRR24422501_1.fastq.gz	Fastqsanger.gz
	SRR24422501_2.fastq.gz	Fastqsanger.gz
	SRR24422502_1.fastq.gz	Fastqsanger.gz

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Chromosomal instability causes sensitivity to polyamines and one-carbon metabolism

Project description:Aneuploidy, having an unbalanced genome, is an aberration commonly found in tumours but rare in normal tissues. 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 investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). Depletion of several of these genes led to cell death by apoptosis in CIN cells, but not normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by loss of SAM synthase in CIN tissues. Loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention like polyamine inhibition has the potential to target CIN tumours via a relatively well characterized mechanism.

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Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism.

Project description:Aneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. 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 investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). The depletion of several of these genes has led to cell death by apoptosis in CIN cells but not in normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by the loss of SAM synthase in CIN tissues. The loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown to contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention such as polyamine inhibition has the potential to target CIN tumours via a relatively well-characterised mechanism.

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Chronic Oxidative DNA Damage Due to DNA Repair Defects Causes Chromosomal Instability in Saccharomyces cerevisiae

Project description:Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, defined as chromosomal instability (CIN). The molecular mechanisms underlying CIN are largely unknown. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage cause chromosomal aberrations at remarkably high frequencies under both selective and non-selective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage results in a “gain of CIN” phenotype and leads to profound karyotypic diversification. These results illustrate a novel mechanism for genome destabilization, which is likely to be relevant to human carcinogenesis. Keywords: CGH-array

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Project description: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.

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