Mutant rs189037 in ataxia-telangiectasia mutated gene had a negative association with metabolic syndrome but not cognitive decline in centenarians.
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ABSTRACT:
SUBMITTER: Feng L
PROVIDER: S-EPMC10825438 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
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Mutant <i>rs189037</i> in <i>ataxia-telangiectasia mutated</i> gene had a negative association with metabolic syndrome but not cognitive decline in centenarians.
Feng Long L Huo Hongqi H Li Qun Q Yang Tao T Zhao Yali Y Zhang Pei P Ping Ping P Fu Shihui S
Genes & diseases 20230802 3
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Project description:In the current study, we aimed to determine the association of single nucleotide polymorphism rs189037 in ataxia-telangiectasia mutated (ATM) gene with cardiac structure and human longevity. Based on the China Hainan Centenarian Cohort Study performed in 18 cities and counties of Hainan Province, China, the current study enrolled 547 centenarians, 250 young participants aged 20-45 years, and 250 middle-aged and elderly participants aged 46-90 years. The frequency of TT genotype was significantly higher and that of CC genotype was significantly lower in middle-aged and elderly participants than in young (P = 0.012) and centenarian (P = 0.041) participants. There were no significant differences in the genotype and allele frequencies of SNP rs189037 between young and centenarian participants. Compared with CT genotype, TT genotype was positively and significantly associated with interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT) in centenarian (IVST: P = 0.049; LVPWT: P = 0.047) and middle-aged and elderly (IVST: P = 0.008; LVPWT: P = 0.004) participants. Compared with CC genotype, TT genotype was positively and significantly associated with LVPWT in centenarian (P = 0.030) and middle-aged and elderly (P = 0.013) participants. Compared with CC genotype, CT genotype was negatively and significantly associated with left ventricular end-diastolic diameter (LVEDD) in centenarian (P = 0.011) and middle-aged and elderly (P = 0.040) participants. The current study demonstrated that mutant rs189037 in the ATM gene was more commonly identified in middle-aged and elderly participants than in young and centenarian participants, was significantly associated with increased left ventricular wall thickness and volume, and could induce left ventricular eccentric hypertrophy and shorten human lifespan. Therefore, rs189037 without mutation might be an indicator of youth health and successful aging, whereas mutant rs189037 might hinder human longevity.
| S-EPMC8187557 | biostudies-literature
Project description:The histone variant H2AX is rapidly phosphorylated at the sites of DNA double-strand breaks (DSBs). This phosphorylated H2AX (gamma-H2AX) is involved in the retention of repair and signaling factor complexes at sites of DNA damage. The dependency of this phosphorylation on the various PI3K-related protein kinases (in mammals, ataxia telangiectasia mutated and Rad3-related [ATR], ataxia telangiectasia mutated [ATM], and DNA-PKCs) has been a subject of debate; it has been suggested that ATM is required for the induction of foci at DSBs, whereas ATR is involved in the recognition of stalled replication forks. In this study, using Arabidopsis as a model system, we investigated the ATR and ATM dependency of the formation of gamma-H2AX foci in M-phase cells exposed to ionizing radiation (IR). We find that although the majority of these foci are ATM-dependent, approximately 10% of IR-induced gamma-H2AX foci require, instead, functional ATR. This indicates that even in the absence of DNA replication, a distinct subset of IR-induced damage is recognized by ATR. In addition, we find that in plants, gamma-H2AX foci are induced at only one-third the rate observed in yeasts and mammals. This result may partly account for the relatively high radioresistance of plants versus yeast and mammals.
| S-EPMC1087258 | biostudies-literature
Project description:BackgroundUp to 40% of lung adenocarcinoma have been reported to lack ataxia-telangiectasia mutated (ATM) protein expression. We asked whether ATM-deficient lung cancer cell lines are sensitive to poly-ADP ribose polymerase (PARP) inhibitors and determined the mechanism of action of olaparib in ATM-deficient A549 cells.MethodsWe analysed drug sensitivity data for olaparib and talazoparib in lung adenocarcinoma cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) project. We deleted ATM from A549 lung adenocarcinoma cells using CRISPR/Cas9 and determined the effects of olaparib and the ATM/Rad3-related (ATR) inhibitor VE-821 on cell viability.ResultsIC50 values for both olaparib and talazoparib positively correlated with ATM mRNA levels and gene amplification status in lung adenocarcinoma cell lines. ATM mutation was associated with a significant decrease in the IC50 for olaparib while a similar trend was observed for talazoparib. A549 cells with deletion of ATM were sensitive to ionising radiation and olaparib. Olaparib induced phosphorylation of DNA damage markers and reversible G2 arrest in ATM-deficient cells, while the combination of olaparib and VE-821 induced cell death.ConclusionsPatients with tumours characterised by ATM-deficiency may benefit from treatment with a PARP inhibitor in combination with an ATR inhibitor.
| S-EPMC6889280 | biostudies-literature
Project description:Ataxia telangiectasia mutated (ATM) acts as a defense against a variety of bone marrow (BM) stressors. We hypothesized that ATM loss in BM-hematopoietic stem cells (HSCs) would be detrimental to both HSC function and microvascular repair while sustained ATM would be beneficial in disease models of diabetes. Chronic diabetes represents a condition associated with HSC depletion and inadequate vascular repair. Gender mismatched chimeras of ATM(-/-) on wild type background were generated and a cohort were made diabetic using streptozotocin (STZ). HSCs from the STZ-ATM(-/-) chimeras showed (a) reduced self-renewal; (b) decreased long-term repopulation; (c) depletion from the primitive endosteal niche; (d) myeloid bias; and (e) accelerated diabetic retinopathy (DR). To further test the significance of ATM in hematopoiesis and diabetes, we performed microarrays on circulating angiogenic cells, CD34(+) cells, obtained from a unique cohort of human subjects with long-standing (>40 years duration) poorly controlled diabetes that were free of DR. Pathway analysis of microarrays in these individuals revealed DNA repair and cell-cycle regulation as the top networks with marked upregulation of ATM mRNA compared with CD34(+) cells from diabetics with DR. In conclusion, our study highlights using rodent models and human subjects, the critical role of ATM in microvascular repair in DR.
| S-EPMC5125377 | biostudies-literature
Project description:Ataxia-telangiectasia mutated (ATM), a master kinase of the DNA damage response (DDR), phosphorylates a multitude of substrates to activate signaling pathways after DNA double-strand breaks (DSBs). ATM inhibitors have been evaluated as anticancer drugs to potentiate the cytotoxicity of DNA damage-based cancer therapy. ATM is also involved in autophagy, a conserved cellular process that maintains homeostasis by degrading unnecessary proteins and dysfunctional organelles. In this study, we report that ATM inhibitors (KU-55933 and KU-60019) provoked accumulation of autophagosomes and p62 and restrained autolysosome formation. Under autophagy-inducing conditions, the ATM inhibitors caused excessive autophagosome accumulation and cell death. This new function of ATM in autophagy was also observed in numerous cell lines. Repression of ATM expression using an siRNA inhibited autophagic flux at the autolysosome formation step and induced cell death under autophagy-inducing conditions. Taken together, our results suggest that ATM is involved in autolysosome formation and that the use of ATM inhibitors in cancer therapy may be expanded.
| S-EPMC10468418 | biostudies-literature
Project description:PurposeMYC transcription factor has critical roles in cell growth, proliferation, metabolism, differentiation, transformation and angiogenesis. MYC overexpression is seen in about 15% of breast cancers and linked to aggressive phenotypes. MYC overexpression also induces oxidative stress and replication stress in cells. ATM signalling and ATR-mediated signalling are critical for MYC-induced DNA damage response. Whether ATM and ATR expressions influence clinical outcomes in MYC overexpressed breast cancers is unknown.MethodsWe investigated ATM, ATR and MYC at the transcriptional level [Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1950)] and at the protein level in the Nottingham series comprising 1650 breast tumours. We correlated ATM, ATR and MYC expressions to clinicopathological features and survival outcomes.ResultsIn MYC over expressed tumours, high ATR or low ATM levels were associated with aggressive breast cancer features such as higher tumour grade, de-differentiation, pleomorphism, high mitotic index, high-risk Nottingham Prognostic Index, triple negative and basal-like breast cancers (all adjusted p values < 0.05). Tumours with low ATM or high ATR levels in conjunction with MYC overexpression also have worse overall breast cancer-specific survival (BCSS) (p value < 0.05).ConclusionsWe conclude that ATR/ATM-directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer.
| S-EPMC6491658 | biostudies-literature
Project description:The reversible phosphorylation of proteins on serine, threonine, and tyrosine residues is an important biological regulatory mechanism. In the context of genome integrity, signaling cascades driven by phosphorylation are crucial for the coordination and regulation of DNA repair. The two serine/threonine protein kinases ataxia telangiectasia-mutated (ATM) and Ataxia telangiectasia-mutated and Rad3-related (ATR) are key factors in this process, each specific for different kinds of DNA lesions. They are conserved across eukaryotes, mediating the activation of cell-cycle checkpoints, chromatin modifications, and regulation of DNA repair proteins. We designed a novel mass spectrometry-based phosphoproteomics approach to study DNA damage repair in Arabidopsis thaliana. The protocol combines filter aided sample preparation, immobilized metal affinity chromatography, metal oxide affinity chromatography, and strong cation exchange chromatography for phosphopeptide generation, enrichment, and separation. Isobaric labeling employing iTRAQ (isobaric tags for relative and absolute quantitation) was used for profiling the phosphoproteome of atm atr double mutants and wild type plants under either regular growth conditions or challenged by irradiation. A total of 10,831 proteins were identified and 15,445 unique phosphopeptides were quantified, containing 134 up- and 38 down-regulated ATM/ATR dependent phosphopeptides. We identified known and novel ATM/ATR targets such as LIG4 and MRE11 (needed for resistance against ionizing radiation), PIE1 and SDG26 (implicated in chromatin remodeling), PCNA1, WAPL, and PDS5 (implicated in DNA replication), and ASK1 and HTA10 (involved in meiosis).
| S-EPMC4349977 | biostudies-literature
Project description:The ataxia-telangiectasia mutated (ATM) protein kinase has been extensively studied for its role in the DNA damage response and its association with the disease ataxia telangiectasia. There is increasing evidence that ATM also plays an important role in other cellular processes, including carbon metabolism. Carbon metabolism is highly dysregulated in cancer due to the increased need for cellular biomass. A number of recent studies report a non-canonical role for ATM in the regulation of carbon metabolism. This review highlights what is currently known about ATM's regulation of carbon metabolism, the implication of these pathways in cancer, and the development of ATM inhibitors as therapeutic strategies for cancer.
| S-EPMC5712564 | biostudies-other
Project description:The ataxia-telangiectasia mutated (ATM) protein plays a central role in DNA damage response and cell cycle checkpoints, and may be a promising target for cancer therapy if normal tissue toxicity could be avoided. The strategy presented here to target ATM for breast cancer therapy involves the use of liposomal-encapsulated, gene-specific ATM siRNA delivered with a well-characterized porous silicon-based multistage vector (MSV) delivery system (MSV/ATM). Biweekly treatment of MSV/ATM suppressed ATM expression in tumor tissues, and consequently inhibited growth of MDA-MB-231 orthotopic tumor in nude mice. At the therapeutic dosage, neither free liposomal ATM siRNA nor MSV/ATM triggered an acute immune response in BALB/c mice, including changes in serum cytokines, chemokines or colony-stimulating factors. Weekly treatments of mice with free liposomal ATM siRNA or MSV/ATM for 4 weeks did not cause significant changes in body weight, hematology, blood biochemistry, or major organ histology. These results indicate that MSV/ATM is biocompatible and efficacious in inhibiting tumor growth, and that further preclinical evaluation is warranted for the development of MSV/ATM as a potential therapeutic agent.
| S-EPMC3842236 | biostudies-literature
Project description:Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro. OA did not induce gamma-H2AX foci, suggesting that it induces ATM autophosphorylation by inactivation of a protein phosphatase rather than by inducing DNA double-strand breaks. In support of this, we show that ATM interacts with the scaffolding (A) subunit of protein phosphatase 2A (PP2A), that the scaffolding and catalytic (C) subunits of PP2A interact with ATM in undamaged cells and that immunoprecipitates of ATM from undamaged cells contain PP2A-like protein phosphatase activity. Moreover, we show that IR induces phosphorylation-dependent dissociation of PP2A from ATM and loss of the associated protein phosphatase activity. We propose that PP2A plays an important role in the regulation of ATM autophosphorylation and activity in vivo.
| S-EPMC526470 | biostudies-literature