Enhanced glutathione levels confer resistance to apoptotic and ferroptotic programmed cell death in NEIL DNA glycosylase deficient HAP1 cells
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ABSTRACT:
PROVIDER: PRJNA1013047 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25918500_1.fastq.gz | Fastqsanger.gz | |||
| SRR25918500_2.fastq.gz | Fastqsanger.gz | |||
| SRR25918501_1.fastq.gz | Fastqsanger.gz | |||
| SRR25918501_2.fastq.gz | Fastqsanger.gz | |||
| SRR25918502_1.fastq.gz | Fastqsanger.gz |
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Project description:The NTHL1 and NEIL1-3 DNA glycosylases are major enzymes in the removal of oxidative DNA base lesions, via the base excision repair (BER) pathway. To investigate their interplay in human cells, we engineered single, double, triple, and quadruple DNA glycosylase deficient HAP1 cells using the Crisp-cas 9 technology. We found that these DNA glycosylase deficient cells are more resistant to oxidative stress caused by genotoxic agents than wild type cells, and a further augment in resistance was observed upon inhibition of glutathione synthesis. Gene expression analysis revealed that GSH depletion activates the NRF2/KEAP1 pathway and ER stress induced apoptosis. Furthermore, glutathione depleted NEIL triple KO cells are also more resistant to cell death induced via ferroptosis than wild type cells. Finally, we observed higher basal level of glutathione and differential expression of NRF2-regulated genes associated with glutathione homeostasis in these cells. We propose that NEIL deficiency leads to aberrant transcription and subsequent errors in protein synthesis, which cause ER- and proteotoxic stress. This triggers the unfolded protein response, which consequently upregulates intracellular antioxidant defence mechanisms. Altogether, our data suggest that NEIL deficient cells developed an oxidative stress defence mechanism termed hormesis mediated by elevated GSH levels in response to the increased intracellular stress inflicted by loss of NEIL123 activities.
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Project description:Enhanced glutathione levels confer resistance to apoptotic and ferroptotic programmed cell death in NEIL DNA glycosylase deficient HAP1 cells
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Project description:Alterations of metabolic and biological processes occur in ferroptotic cells. We analyzed transcriptional responses of murine embryonic fibroblasts (MEFs) exposed to a ferroptosis inducer erastin. We found that a set of genes related to protection against oxidative stress was induced upon ferroptosis and Bach1 promoted ferroptosis by repressing a set of these genes involved in synthesis of glutathione or metabolism of intracellular labile iron. Our findings suggests that ferroptosis is programmed at transcriptional level and Bach1 works as a controller in setting a threshold of ferroptosis.
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Project description:Pfa1 cells undergo ferroptosis upon induction of knockout of the glutathione peroxidase 4 via tamoxifen treatment. Ferroptosis is a recently discovered, iron-dependent mode of cell death, whose potency to evoke an immune response in the surrounding tissue remains to be clarified. The goal of this project is to analyze newly translated protein components in the secretome of ferroptotic Pfa1 cells in order to identify immunogenic components on the protein level via a click chemistry based approach
2025-04-24 | PXD050979 | Pride
Project description:To investigate ferroptosis-dependent changes in DNA methylation, a genome wide DNA methylation profiling of ferroptotic (RSL3-treated) multiple myeloma cells (MM1S & MM1R) was performed using the 850K MethylationEPIC BeadChip Array. The ferroptotic DNA methylation signature was compared to myeloma cells pre-treated with the ferroptosis inhibitor ferrostatin-1 (FRSL3), which served as a negative control. In total, three biological replicates per treatment per cell line were included.
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Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. While ferroptosis has been identified as a mechanism for suppressing cancer, its overall physiological significance remains poorly understood. Recent studies have revealed that labile iron and lipid peroxides are released from ferroptotic cells, leading to the propagation of ferroptosis through lipid peroxidation. However, other specific effects of secreted factors derived from ferroptotic cells remain unclear. We constructed a model cell system capable of inducing ferroptosis by re-expressing the transcription factor BACH1, a potent inducer of ferroptosis, in immortalized mouse embryonic fibroblasts (iMEFs). We investigated the impact of the secreted factors from ferroptotic cells with the iMEFs. As a result, we observed that the administration of supernatant media from ferroptotic iMEFs activated proliferation of hepatoma cells and suppressed cellular senescence-like features. This suggested that ferroptotic MEFs secrete anti-senescent substances. Transcriptome analysis of ferroptotic MEFs revealed an increase in the secretion of longevity factor FGF21 in a BACH1-dependent manner. Furthermore, the anti-senescent effects of the supernatant media from these ferroptotic cells were canceled by the knockout of Fgf21. Totally, it is suggested that BACH1 promotes ferroptosis in fibroblasts and contributes to the suppression of cellular senescence in neighboring cells by inducing FGF21 secretion from fibroblasts. It was also discovered that BACH1 not only activates indirectly the transcription of FGF21 by enhancing ferroptotic stress but also increases FGF21 protein level by suppressing the selective autophagic degradation of FGF21 through the transcriptional repression for Sqstm1 and Lamp2a. This represents a dual mechanism of FGF21 upregulation mediated by BACH1, suggesting that BACH1 is a potent inducer of FGF21 expression. It was also found that the BACH1-ferroptosis-FGF21 axis can suppress obesity of mice under high fat diet or short lifespan of progeria mice, closely associated phenotypes with aging. The inhibition of these aging-related phenotypes is considered to be a novel physiological significance of ferroptosis, and BACH1 is considered to function as a longevity gene by promoting ferroptotsis and subsequent FGF21 expression.
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Project description:The nematode Caenorhabditis elegans has been used extensively to study responses to DNA damage. In contrast, little is known about DNA repair in this organism. C. elegans is unusual in that it encodes few DNA glycosylases and the uracil-DNA glycosylase (UDG) encoded by the ung-1 gene is the only known UDG. C. elegans could therefore become a valuable model organism for studies of the genetic interaction networks involving base excision repair (BER). As a first step towards characterization of BER in C. elegans, we show that the UNG-1 protein is an active uracil-DNA glycosylase. We demonstrate that an ung-1 mutant has reduced ability to repair uracil-containing DNA but that an alternative Ugi-inhibited activity is present in ung-1 nuclear extracts. Finally, we demonstrate that ung-1 mutants show altered levels of apoptotic cell corpses formed in response to DNA damaging agents. Increased apoptosis in the ung-1 mutant in response to ionizing radiation (IR) suggests that UNG-1 contributes to repair of IR-induced DNA base damage in vivo. Following treatment with paraquat however, the apoptotic corpse-formation was reduced. Gene expression profiling suggests that this phenotype is a consequence of compensatory transcriptomic shifts that modulate oxidative stress responses in the mutant and not an effect of reduced DNA damage signaling. C. elegans RNAi mutants deficient in ung-1 and the corresponding wild-type N2, were subjected to Affymetrix whole C. elegans genome microarrays. Triplicates were run for each sample group.
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Project description:The objective is to understand how the transcriptome of dendritic cells changes after the uptake of ferroptotic cells.
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Project description:The nematode Caenorhabditis elegans has been used extensively to study responses to DNA damage. In contrast, little is known about DNA repair in this organism. C. elegans is unusual in that it encodes few DNA glycosylases and the uracil-DNA glycosylase (UDG) encoded by the ung-1 gene is the only known UDG. C. elegans could therefore become a valuable model organism for studies of the genetic interaction networks involving base excision repair (BER). As a first step towards characterization of BER in C. elegans, we show that the UNG-1 protein is an active uracil-DNA glycosylase. We demonstrate that an ung-1 mutant has reduced ability to repair uracil-containing DNA but that an alternative Ugi-inhibited activity is present in ung-1 nuclear extracts. Finally, we demonstrate that ung-1 mutants show altered levels of apoptotic cell corpses formed in response to DNA damaging agents. Increased apoptosis in the ung-1 mutant in response to ionizing radiation (IR) suggests that UNG-1 contributes to repair of IR-induced DNA base damage in vivo. Following treatment with paraquat however, the apoptotic corpse-formation was reduced. Gene expression profiling suggests that this phenotype is a consequence of compensatory transcriptomic shifts that modulate oxidative stress responses in the mutant and not an effect of reduced DNA damage signaling.
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