Histone H2A variants: Diversifying chromatin to ensure genome integrity

Seminars in Cell and Developmental Biology, Год журнала: 2022, Номер 135, С. 59 - 72

Опубликована: Март 21, 2022

Язык: Английский

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DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6313 - 6313

Опубликована: Март 28, 2023

Parkinson’s disease (PD) is the second most common neurodegenerative around world; however, its pathogenesis remains unclear so far. Recent advances have shown that DNA damage and repair deficiency play an important role in pathophysiology of PD. There growing evidence suggesting involved propagation cellular PD, leading to neuropathology under different conditions. Here, we reviewed current work on First, outlined causes Second, described potential pathways by which mediates neurotoxicity PD discussed precise mechanisms drive these processes damage. In addition, looked ahead interventions targeting repair. Finally, based status research, key problems need be addressed future research were proposed.

Язык: Английский

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Structural insights into the activation of ataxia-telangiectasia mutated by oxidative stress

Science Advances, Год журнала: 2023, Номер 9(39)

Опубликована: Сен. 27, 2023

Ataxia-telangiectasia mutated (ATM) is a master kinase regulating DNA damage response that activated by double-strand breaks. However, ATM also directly reactive oxygen species, but how oxidative activation achieved remains unknown. We determined the cryo-EM structure of an H2O2-activated and showed under oxidizing conditions, formed intramolecular disulfide bridge between two protomers are rotated relative to each other when compared basal state. This rotation accompanied release substrate-blocking PRD region twisting N-lobe C-lobe, which greatly optimizes catalysis. active site remodeling enabled us capture substrate (p53) bound enzyme. provides first structural insights into during stress.

Язык: Английский

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Beta-elemene: A phytochemical with promise as a drug candidate for tumor therapy and adjuvant tumor therapy

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 172, С. 116266 - 116266

Опубликована: Фев. 13, 2024

β-Elemene (IUPAC name: (1 S,2 S,4 R)-1-ethenyl-1-methyl-2,4-bis(prop-1-en-2-yl) cyclohexane), is a natural compound found in turmeric root. Studies have demonstrated its diverse biological functions, including anti-tumor properties, which been extensively investigated. However, these not yet reviewed. The aim of this review was to provide comprehensive summary β-elemene research, with respect disease treatment.

Язык: Английский

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Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization

Science Translational Medicine, Год журнала: 2024, Номер 16(734)

Опубликована: Фев. 14, 2024

ATM is a key mediator of radiation response, and pharmacological inhibition rational strategy to radiosensitize tumors. AZD1390 brain-penetrant inhibitor potent radiosensitizer. This study evaluated the spectrum radiosensitizing effects impact TP53 mutation status in panel IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). suppressed radiation-induced signaling, abrogated G 0 -G 1 arrest, promoted proapoptotic response specifically p53-mutant GBM vitro. In preclinical trial using 10 orthotopic models, AZD1390/RT afforded benefit cohort -mutant tumors but not -WT PDXs. mechanistic studies, increased endogenous DNA damage constitutive signaling were observed -mutant, -WT, plasmid-based reporter assays, GBM43 ( -mutant) showed elevated repair capacity compared with that GBM14 (p53-WT), whereas treatment homologous recombination (HR) efficiency, part, by stalling RAD51 unloading. Furthermore, overexpression dominant-negative (p53DD) construct resulted enhanced basal HR activity, AZD1390-mediated radiosensitization GBM14. Analyzing RNA-seq data from TCGA up-regulation pathway genes human GBM. Together, our results imply dependence on represent unique susceptibility cells inhibitor–mediated radiosensitization.

Язык: Английский

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ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies

Blood, Год журнала: 2024, Номер 144(11), С. 1193 - 1205

Опубликована: Июнь 25, 2024

Язык: Английский

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The cGAS–STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(2)

Опубликована: Янв. 7, 2025

Ataxia–telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of homeostatic protein kinase ATM. The complex phenotype A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts patients exhibit senescence, highlighting association between cellular We found that derived ATM-deficient mice provide versatile experimental system to explore mechanisms driving senescence primary lacking Atm −/− failed proliferate under ambient oxygen conditions (21%). Although they initially proliferated physiological levels (3%), rapidly entered senescence. In contrast, wild-type (WT) did not senesce 3% eventually underwent immortalization neoplastic transformation. However, rapid could be induced in WT cells either by gene ablation or persistent chemical inhibition ATM activity, with being reversible upon inhibitor removal. Moreover, concomitant p53 led evasion, vigorous growth, rampant subsequent Our findings reveal driven collaborative action cGAS–STING, p38 MAPK, pathways response DNA damage, ultimately leading induction interferon-α1 downstream interferon-stimulated genes. propose accelerated may exacerbate specific symptoms, particularly contributing progressive, life-threatening disease often observed during adulthood.

Язык: Английский

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Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition

Redox Biology, Год журнала: 2025, Номер 80, С. 103503 - 103503

Опубликована: Янв. 19, 2025

Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic confer DDR inhibition cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen identified genetic vulnerabilities We unveiled Peroxiredoxin 1 (PRDX1) synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity ATM vitro mice manner dependent on p53 status. Mechanistically, discovered that the ribosomal protein RPL32 undergoes redox modification active cysteine residues 91 96 upon inhibition, promoting stability altered cell fitness. Our findings reveal new pathway whereby senses induces activation impairing survival.

Язык: Английский

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Phosphorylated BLM peptide acts as an agonist for DNA damage response

Nucleic Acids Research, Год журнала: 2025, Номер 53(4)

Опубликована: Фев. 8, 2025

Abstract Upon exposure to ionizing irradiation, the MRE11–RAD50–NBS1 complex potentiates recruitment of ATM (ataxia-telangiectasia mutated) kinase double-strand breaks. We show that lack BLM causes a decrease in autophosphorylation mice mammary glands, which have lost one or both copies BLM. In isogenic human cells, DNA damage response (DDR) pathway was dampened absence BLM, negatively affected DDR factors onto chromatin, thereby indicating direct role augmenting DDR. Mechanistically, this due BLM-dependent dissociation inactive dimers into active monomers. Fragmentation analysis followed by assays revealed 20-mer peptide (91–110 aa), sufficient enhance ATM-dependent p53 phosphorylation. ATM-mediated phosphorylation at Thr99 within (91–110) enhanced activity its interaction with NBS1 and causing monomerization. Delivery phosphomimetic T99E counterpart aa) led activation restoration even irradiation (both cells knockout mice), as agonist, can be potentially used prevent initiation neoplastic transformation.

Язык: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Язык: Английский

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