Similar Datasets
Project description:Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL). But in clinical trials, pan-Notch inhibitors caused excessive toxicity. To find alternative ways to target Notch signals, we investigated Cell division cycle 73 (Cdc73), which is a component of the RNA polymerase-associated transcriptional machinery and has been previously described as a Notch cofactor. Emerging evidence also suggests that transcriptional machinery might be an attractive vulnerability in T-ALL. In this setting, we show that CDC73 co-binds a subset of Notch-occupied regulatory elements in an ETS1-dependent context. In mouse models, Cdc73 is important for Notch-induced T-cell development and maintenance of Notch-induced T-ALL. Mechanistically, Cdc73, Ets1, and Notch activate genes that promote DNA repair and oxidative phosphorylation. Cdc73 induces these pathways through canonical functions in mRNA synthesis rather than non-canonical functions in enhancer activation. Our study suggests that Cdc73 acts through context-dependent mechanisms to promote a gene expression program that mitigates the genotoxic and metabolic stress of supraphysiological Notch signaling. We also provide mechanistic support for testing inhibitors of DNA repair, oxidative phosphorylation, and transcriptional machinery as anti-leukemic therapy while highlighting strategies that disable pathways that intersect with Notch at chromatin to target Notch signals without directly targeting the Notch complex.
2023-08-30 | GSE221339 | GEO
Project description:Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL). But in clinical trials, pan-Notch inhibitors caused excessive toxicity. To find alternative ways to target Notch signals, we investigated Cell division cycle 73 (Cdc73), which is a component of the RNA polymerase-associated transcriptional machinery and has been previously described as a Notch cofactor. Emerging evidence also suggests that transcriptional machinery might be an attractive vulnerability in T-ALL. In this setting, we show that CDC73 co-binds a subset of Notch-occupied regulatory elements in an ETS1-dependent context. In mouse models, Cdc73 is important for Notch-induced T-cell development and maintenance of Notch-induced T-ALL. Mechanistically, Cdc73, Ets1, and Notch activate genes that promote DNA repair and oxidative phosphorylation. Cdc73 induces these pathways through canonical functions in mRNA synthesis rather than non-canonical functions in enhancer activation. Our study suggests that Cdc73 acts through context-dependent mechanisms to promote a gene expression program that mitigates the genotoxic and metabolic stress of supraphysiological Notch signaling. We also provide mechanistic support for testing inhibitors of DNA repair, oxidative phosphorylation, and transcriptional machinery as anti-leukemic therapy while highlighting strategies that disable pathways that intersect with Notch at chromatin to target Notch signals without directly targeting the Notch complex.
2023-08-30 | GSE219097 | GEO
Project description:Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress
| PRJNA913927 | ENA
Project description:Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress [ChIP-seq]
| PRJNA913932 | ENA
Project description:Cdc73 protects Notch-induced T-cell leukemia cells from DNA damage and mitochondrial stress [Bru-seq and BruUV-seq]
| PRJNA907026 | ENA
Project description:Oxygen is not only required for oxidative phosphorylation but also serves as the essential substrate for the formation of reactive oxygen species (ROS), which is implicated in ageing and tumorigenesis. Although the mitochondrion is known for its bioenergetic function, the symbiotic theory originally proposed that it provided protection against the toxicity of increasing oxygen in the primordial atmosphere. Using human cells lacking Synthesis of Cytochrome c Oxidase 2 (SCO2-/-), we have tested the oxygen toxicity hypothesis. These cells are oxidative phosphorylation defective and glycolysis dependent; they exhibit increased viability under hypoxia and feature an inverted growth response to oxygen compared with wild-type cells. SCO2-/- cells have increased intracellular oxygen and nicotinamide adenine dinucleotide (NADH) levels, which result in increased ROS and oxidative DNA damage. Using this isogenic cell line, we have revealed the genotoxicity of ambient oxygen. Our study highlights the importance of mitochondrial respiration both for bioenergetic benefits and for maintaining genomic stability in an oxygen-rich environment.
| S-EPMC3393093 | biostudies-literature
Project description:Exercise simultaneously incites beneficial (e.g., signal) and harming (e.g., damage to macromolecules) effects, likely through the generation of reactive oxygen and nitrogen species (RONS) and downstream changes to redox homeostasis. Given the link between nuclear DNA damage and human longevity/pathology, research attempting to modulate DNA damage and restore redox homeostasis through non-selective pleiotropic antioxidants has yielded mixed results. Furthermore, until recently the role of oxidative modifications to mitochondrial DNA (mtDNA) in the context of exercising humans has largely been ignored. The development of antioxidant compounds which specifically target the mitochondria has unveiled a number of exciting avenues of exploration which allow for more precise discernment of the pathways involved with the generation of RONS and mitochondrial oxidative stress. Thus, the primary function of this review, and indeed its novel feature, is to highlight the potential roles of mitochondria-targeted antioxidants on perturbations to mitochondrial oxidative stress and the implications for exercise, with special focus on mtDNA damage. A brief synopsis of the current literature addressing the sources of mitochondrial superoxide and hydrogen peroxide, and available mitochondria-targeted antioxidants is also discussed.
| S-EPMC7698504 | biostudies-literature
Project description:Klotho is an anti-aging, single-pass transmembrane protein found mainly in the kidney. Although aging is likely to be associated with DNA damage, the involvement of Klotho in protecting cells from DNA damage is still unclear. In this study, we examined DNA damage in human kidney cells and mouse kidney tissue after ionizing radiation (IR). The depletion and overexpression of Klotho in human kidney cells reduced and increased the cell survival rates after IR, respectively. The formation of γ-H2AX foci, representing DNA damage, was significantly elevated immediately after IR in cells with Klotho depletion and decreased in cells overexpressing Klotho. These results were confirmed in mouse renal tissues after IR. Quantification of DNA damage by a comet assay revealed that the Klotho knockdown significantly increased the amount of DNA damage immediately after IR, suggesting that Klotho protects chromosomal DNA from the induction of damage, rather than facilitating DNA repair. Consistent with this notion, Klotho was detected in both the nucleus and cytoplasm. In the nucleus, Klotho may serve to protect chromosomal DNA from damage, leading to its anti-aging effects.
| S-EPMC10129345 | biostudies-literature
Project description:Oxidative stress and iron accumulation are tightly associated with neurodegenerative diseases. Mitochondrial ferritin (FtMt) is identified as an iron-storage protein located in the mitochondria, and its role in regulation of iron hemeostasis in neurodegenerative diseases has been reported. However, the role of FtMt in hydrogen peroxide (H2O2)-induced oxidative stress and iron accumulation in neuronal cells has not been studied. Here, we overexpressed FtMt in neuroblastoma SH-SY5Y cells and induced oxidative stress by treating with extracellular H2O2. We found that overexpression of FtMt significantly prevented cell death induced by H2O2, particularly the apoptosis-dependent cell death. The protective effects involved inhibiting the generation of cellular reactive oxygen species, sustaining mitochondrial membrane potential, maintaining the level of anti-apoptotic protein Bcl-2, and inhibiting the activation of pro-apoptotic protein caspase 3. We further explored the mechanism of these protective effects and found that FtMt expression markedly altered iron homeostasis of the H2O2 treated cells as compared to that of controls. The FtMt overexpression significantly reduced cellular labile iron pool (LIP) and protected H2O2-induced elevation on LIP. While in H2O2 treated SH-SY5Y cells, the increased iron uptake and reduced iron release, in correlation with levels of DMT1(-IRE) and ferroportin 1, resulted in heavy iron accumulation, the FtMt overexpressing cells didn't show any significant changes in levels of iron transport proteins and in the level of LIP. These results implicate a neuroprotective role of FtMt on H2O2-induced oxidative stress, which may provide insights into the treatment of iron accumulation associated neurodegenerative diseases.
| S-EPMC5524808 | biostudies-other
Project description:The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology2,3. We showed previously that instability and cytoplasmic release of mtDNA activates the cGAS-STING-TBK1 pathway resulting in interferon stimulated gene (ISG) expression that promotes antiviral immunity4. Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. Instead, a specific subset of ISGs, that includes Parp9, remains activated by the unphosphorylated form of ISGF3 (U-ISGF3) that enhances nDNA damage and repair responses. In cultured primary fibroblasts and cancer cells, the chemotherapeutic drug doxorubicin causes mtDNA damage and release, which leads to cGAS-STING-dependent ISG activation. In addition, mtDNA stress in TFAM-deficient mouse melanoma cells produces tumours that are more resistant to doxorubicin in vivo. Finally, Tfam +/- mice exposed to ionizing radiation exhibit enhanced nDNA repair responses in spleen. Therefore, we propose that damage to and subsequent release of mtDNA elicits a protective signalling response that enhances nDNA repair in cells and tissues, suggesting mtDNA is a genotoxic stress sentinel.
| S-EPMC7213273 | biostudies-literature