ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair. EMBO J

Genome Stability Unit, Clare Laboratories, London Research Institute, Cancer Research UK, South Mimms, UK.
The EMBO Journal (Impact Factor: 10.43). 02/2011; 30(3):546-55. DOI: 10.1038/emboj.2010.330
Source: PubMed


Ataxia telangiectasia (A-T) is a human disease caused by ATM deficiency characterized among other symptoms by radiosensitivity, cancer, sterility, immunodeficiency and neurological defects. ATM controls several aspects of cell cycle and promotes repair of double strand breaks (DSBs). This probably accounts for most of A-T clinical manifestations. However, an impaired response to reactive oxygen species (ROS) might also contribute to A-T pathogenesis. Here, we show that ATM promotes an anti-oxidant response by regulating the pentose phosphate pathway (PPP). ATM activation induces glucose-6-phosphate dehydrogenase (G6PD) activity, the limiting enzyme of the PPP responsible for the production of NADPH, an essential anti-oxidant cofactor. ATM promotes Hsp27 phosphorylation and binding to G6PD, stimulating its activity. We also show that ATM-dependent PPP stimulation increases nucleotide production and that G6PD-deficient cells are impaired for DSB repair. These data suggest that ATM protects cells from ROS accumulation by stimulating NADPH production and promoting the synthesis of nucleotides required for the repair of DSBs.

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Available from: Domenico Grieco, Mar 05, 2014
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    • "In addition to DNA repair pathways, only BPDE activated the pentose phosphate pathway (PPP) and the ATM-dependent DNA damage response. Both pathways were shown to closely cooperate in response to doublestrand breaks (DSB) in DNA: ATM recruits and activates the PPP pathway, which increases the input of nucleotides to be used during the replacement of damaged DNA bases (Cosentino et al. 2011). Thus, our results suggest that in contrast to BaP, where the cell can quickly adapt to increasing levels of genotoxicant, abrupt stimuli induced by BPDE have resulted in extensive DNA damage which triggered enhanced expression of genes necessary for DNA repair in order to protect the cell against future challenges (Lei et al. 2007). "
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    ABSTRACT: Benzo(a)pyrene (BaP) is a ubiquitous carcinogen resulting from incomplete combustion of organic compounds and also present at high levels in cigarette smoke. A wide range of biological effects has been attributed to BaP and its genotoxic metabolite BPDE, but the contribution to BaP toxicity of intermediary metabolites generated along the detoxification path remains unknown. Here, we report for the first time how 3-OH-BaP, 9,10-diol and BPDE, three major BaP metabolites, temporally relate to BaP-induced transcriptomic alterations in HepG2 cells. Since BaP is also known to induce AhR activation, we additionally evaluated TCDD to source the expression of non-genotoxic AhR-mediated patterns. 9,10-Diol was shown to activate several transcription factor networks related to BaP metabolism (AhR), oxidative stress (Nrf2) and cell proliferation (HIF-1α, AP-1) in particular at early time points, while BPDE influenced expression of genes involved in cell energetics, DNA repair and apoptotic pathways. Also, in order to grasp the role of BaP and its metabolites in chemical hepatocarcinogenesis, we compared expression patterns from BaP(-metabolites) and TCDD to a signature set of approximately nine thousand gene expressions derived from hepatocellular carcinoma (HCC) patients. While transcriptome modulation by TCDD appeared not significantly related to HCC, BaP and BPDE were shown to deregulate metastatic markers via non-genotoxic and genotoxic mechanisms and activate inflammatory pathways (NF-κβ signaling, cytokine-cytokine receptor interaction). BaP also showed strong repression of genes involved in cholesterol and fatty acid biosynthesis. Altogether, this study provides new insights into BaP-induced toxicity and sheds new light onto its mechanism of action as a hepatocarcinogen.
    Archives of Toxicology 08/2015; DOI:10.1007/s00204-015-1572-z · 5.98 Impact Factor
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    • "This suggests that G6PD activity is also regulated by another p53-independent mechanism in shRRM2-expressing cells. Indeed, G6PD activity is known to be positively regulated by ATM-mediated phosphorylation of HSP27 (pHSP27) (Cosentino et al., 2011). Consistently, pHSP27 was increased in shRRM2 cells (Figure S3U), which correlates with activation of ATM by shRRM2 (Figure 1A–B). "
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    ABSTRACT: Replication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM) plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP) levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD) activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(6). DOI:10.1016/j.celrep.2015.04.014 · 8.36 Impact Factor
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    • "The use of antioxidants in ATM null mice has been shown to delay tumor formation.73–76 Reactive oxygen species can directly activate ATM, which in turn promotes antioxidant responses through stimulation of the pentose phosphate pathway, and ATM plays a role in monitoring mitochondrial quality control, again pointing to a central function of ATM in controlling cellular metabolism of reactive oxygen species.47,77 ATM may directly regulate mitochondrial homeostasis through responding to reactive oxygen species or by regulating mitochondrial quality control genes, such as PINK1 or Parkin.46 "
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    ABSTRACT: Ataxia-telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM). ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR) in the event of double strand breaks (DSBs). The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR) or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult to be delivered across the blood-brain barrier at present. As of now, apart from glucocorticoids, use of histone deacetylase inhibitors/EZH2 to minimize effect of the absence of ATM, looks more promising.
    The Application of Clinical Genetics 09/2014; 7:159-67. DOI:10.2147/TACG.S35759
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