Different response to oxidative damage of iPS cells and the progenitor fibroblast cells through the lens of the DNA repair system
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE138093 | GEO | 2019/10/01
REPOSITORIES: GEO
Similar Datasets
Project description:Oxidative DNA damage in neurons activates a DNA damage response (DDR) to promote repair. Under a chronic oxidative environment these processes may be altered and promote accumulation of unrepaired DNA damage and continued activation of a DDR, leading to apoptosis or senescence activation. Accumulation of oxidative DNA damage are features of brain ageing and neurodegeneration but the effects of persistent DNA damage in neurons are not well characterised. We developed a model of persistent oxidative DNA damage in human neurons in vitro (LUHMES) by exposing them to a sub-lethal concentration of hydrogen peroxide (H2O2) following a "single stress" and “double stress” protocols. We characterised the neuronal transcriptome under these circumstances using microarray analysis.
2023-11-04 | GSE160841 | GEO
Project description:p53, master transcriptional regulator of the genotoxic stress response, controls cell cycle arrest and apoptosis following DNA damage. Here we identify a p53-induced lncRNA SPARCLE (Suicidal PARP-1 Cleavage Enhancer) adjacent to miR-34b/c required for p53-mediated apoptosis. SPARCLE is a ~770 nucleotide, nuclear lncRNA induced one day after DNA damage. Despite low expression (<15 copies/cell), SPARCLE deletion increases DNA repair and reduces DNA damage-induced apoptosis as much as p53 deficiency, while its over-expression restores apoptosis in p53-deficient cells. SPARCLE does not alter gene expression. SPARCLE causes apoptosis by acting as a caspase-3 cofactor for PARP-1 cleavage, which separates its N-terminal (NT) DNA binding domain from PARP-1 catalytic domains. NT-PARP-1 binds to DNA breaks but, lacking its PARylation domains, does not initiate DNA repair. In fact, expressing NT-PARP-1 in SPARCLE-deficient cells increases unrepaired DNA damage and restores apoptosis after DNA damage. Thus, as a PARP-1 cleavage cofactor, SPARCLE enhances p53-induced apoptosis.
2022-02-01 | GSE144510 | GEO
Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.
2024-09-02 | BIOMD0000000939 | BioModels
Project description:The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the "apoptotic" steady state is enabled by the existence of a subcritical Neimark-Sacker bifurcation in which the limit cycle loses its stability by merging with an unstable invariant torus. Our analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of Wip1 and PTEN exhibit a broad spectrum of responses to DNA damage: from a fast transition to a high level of p53 killer (a p53 phosphoform which promotes commitment to apoptosis) in cells characterized by high PTEN and low Wip1 levels to long-lasting p53 level oscillations in cells having PTEN promoter methylated (as in, e.g., MCF-7 cell line).
2024-09-02 | BIOMD0000000943 | BioModels
Project description:In double-strand DNA damage repair, non-homologous end joining (NHEJ) is more error prone than homologous recombination repair (HRR), indicating that the relative prevalence of NHEJ may lead to more incorrect repair and thus to increases in chromosome damage. If DNA damage is extensive and cells are unable to repair that damage they typically undergo apoptosis. The mechanism(s) by which cells decide to switch from DNA repair to apoptosis is unknown. Since DNA repair and apoptosis are both energy-demanding processes, the answer may involve ATP utilization. We used human mitochondrial mutant cell lines obtained from people with phenotypic manifestations of compromised ATP generation. We hypothesized that these cells may not have adequate capacity for dealing with the additional demands for ATP required for repairing DNA damage after genotoxic exposure, perhaps making the cells more prone to undergo apoptosis instead of initiating repair. This study describes changes in the expression of genes involved in NHEJ or HRR, as well as genes involved in apoptosis, in one normal and two mitochondrial mutant human cell lines following ionizing radiation exposure. Compared to normal cells, both mutant cell lines showed reduced expression of genes involved in NHEJ and HRR. Analysis of expression changes in genes involved in apoptosis revealed marked increases in expression in the mutants compared to normal cells. These results indicate that following ionizing radiation exposure, mitochondrial mutant cells have decreased levels of mRNA expression of DNA repair genes and increased expression levels of genes involved in apoptosis compared to normal cells. This study provides information that might be useful in characterizing energy dependent processes following exposure to stress or genotoxic agents.
2010-04-24 | GSE21428 | GEO
Project description:There is mounting evidence that mismatch repair (MMR) proteins are involved in oxidative DNA damage response. SETD2, the histone H3K36 tri-methyltransferase, is a newly found factor participate in MMR pathway in human cells. In this study, we show that SETD2 can directly interact with MMR protein MutSα, and they are enriched and colocalized in chromatin in response to oxidative damage, which maybe the reason for the amplification of H3K36me3. Moreover, MutSα and SETD2 are essential for ATM and CHK2 activation upon H2O2 treatment, loss of SETD2 and MutSα will display impaired DNA damage response and oxidative DNA repair, which will accumulate oxidative damage and lead to more cell apoptosis and cell death. Our finding provided a novel SETD2 dependent mechanism for the oxidative DNA damage response together with MMR protein.
2022-07-06 | GSE163940 | GEO
Project description:DNA damage comprises a causal factor for aging and aging-associated diseases. Defects in genome maintenance pathways give rise to a variety of human congenital syndromes that are characterized by growth retardation, cancer susceptibility, and accelerated aging. The specific consequences of unrepaired DNA damage in human diseases are particularly apparent in syndromes caused by distinct nucleotide excision repair (NER) defects, however, with yet poorly understood genotype-phenotype correlations and highly complex disease phenotypes. We have established that the equivalent mutations in the simple metazoan Caenorhabditis elegans reflect the distinct outcomes of DNA repair defects and allow investigating the consequences of persistent DNA damage during animal development and aging. Here, we employed proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment in order to gain comprehensive insights into the full range of physiological adaptations to the presence of unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated protoestatic response. We assign central roles for the IIS regulator DAF-2 and the EGF-signalling pathway in orchestrating this adaptive response to DNA damage. Our results provide new insights into the DNA damage responses in the organismal context.
2017-08-22 | PXD005649 | Pride
Project description:Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function.
2017-09-04 | PXD006648 | Pride
Project description:Unrepaired DNA damage contributes to brain aging and neurodegenerative diseases. However, the factors stimulating DNA repair activity to stave off age-associated functional decline remain obscure. Here, we show that histone deacetylase 1 (HDAC1) modulates DNA repair in the aging brain via targeting OGG1 of the base excision repair pathway. Mice deficient in HDAC1 display age-associated accumulation of DNA damage in the brain and cognitive impairment. HDAC1 interacts with and positively stimulates OGG1, a DNA glycosylase that primarily acts on 8-oxoguanine (8-oxoG), a type of oxidative DNA damage associated with transcriptional repression. Loss of HDAC1 leads to impaired OGG1 activity, 8-oxoG accumulation at the promoters of a subset of genes critical for brain function, and transcriptional repression. Moreover, we observe elevated 8-oxoG lesions along with reduced HDAC1 activity and downregulation of a similar set genes in the 5XFAD mouse model of Alzheimer’s disease (AD). Notably, pharmacological activation of HDAC1 confers protection against the deleterious effects of 8-oxoG lesions in the brains of aged wild-type and 5XFAD mice. Our work uncovers an important role for HDAC1 in the repair of 8-oxoG lesions and highlights HDAC1 activation as a novel therapeutic strategy to counter functional decline during brain aging and neurodegeneration.
2020-03-30 | GSE115437 | GEO
Project description:The cellular response to DNA damage is mediated through multiple pathways that regulate and coordinate DNA repair, cell cycle arrest and cell death. We show that the DNA damage response (DDR) induced by ionizing radiation (IR) is coordinated in breast cancer cells by selective mRNA translation mediated by high levels of translation initiation factor eIF4G1. Increased expression of eIF4G1, common in breast cancers, was found to selectively increase translation of mRNAs involved in cell survival and the DDR, preventing autophagy and apoptosis (Survivin, HIF1α, XIAP), promoting cell cycle arrest (GADD45a, p53, ATRIP, Chk1) and DNA repair (53BP1, BRCA1/2, PARP, Rfc2-5, ATM, MRE-11, others). Reduced expression of eIF4G1, but not its homolog eIF4G2, greatly sensitizes cells to DNA damage by IR, induces cell death by both apoptosis and autophagy, and significantly delays resolution of DNA damage foci with little reduction of overall protein synthesis. While some mRNAs selectively translated by higher levels of eIF4G1 were found to use internal ribosome entry site (IRES)-mediated alternate translation, most do not. The latter group shows significantly reduced dependence on eIF4E for translation, facilitated by an enhanced requirement for eIF4G1. Increased expression of eIF4G1 therefore promotes specialized translation of survival, growth arrest and DDR mRNAs that are important in cell survival and DNA repair following genotoxic DNA damage. The purpose of this study was to identify mRNAs that are selectively increased in translation by high levels of the initiation factor eIF4G1, which occurs in many advanced human cancers, in response to DNA damage caused by ionizing radiation,
2012-10-17 | GSE41627 | GEO