{"id":{"repo_id":"milano","oai_identifier":"oai:air.unimi.it:2434/959076"},"canonical_url":"https://search.dev.ndltd.org/etd/milano/oai:air.unimi.it:2434/959076","repository":{"repo_id":"milano","name":"Università degli Studi di Milano","base_url":"https://air.unimi.it/oai/request"},"display":{"title":"UNDERSTANDING THE MOLECULAR MECHANISM LINKING ATM TO METABOLIC REGULATION.","abstract":"Ataxia Telangiectasia (A-T) is a pleiotropic autosomal recessive disease characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation and premature aging. The molecular basis of A-T is loss of function of the gene encoding A-T-mutated (ATM), a serine/threonine kinase that acts as a master regulator of the DNA damage response, leaving A-T patients highly predisposed to cancers. In addition to its classical role in orchestrating the DNA damage response, recent evidence reports a role for ATM in cellular metabolism, oxidative stress response and insulin signaling. However, it is unclear how defective ATM-dependent response to oxidative stress contributes to A-T clinical manifestations. Here we show that ATM activates glycolysis upon oxidative stress and that its loss leads to impairment of glycolysis and impairment of metabolism in A-T cells. In addition, we identified a metabolic regulator as a major driver of glycolysis impairment and poor cell growth in A-T tissues. Respectively, the downregulation and inactivation of this metabolic regulator in A-T cells restored normal glycolysis, reduced metabolites accumulation and improved A-T cells survival and proliferation. Taken together, our results shed light on a new role of ATM in activating glycolysis and cellular metabolism upon oxidative stress and help to identify a metabolic checkpoint activated in ATM-deficient cells to suppress cellular anabolic pathways and cellular growth. Our study also identified a potential therapeutical target that exerts a synthetic survival effect upon downregulation, to slow down the progression and symptoms of A-T disease.","abstract_html":"Ataxia Telangiectasia (A-T) is a pleiotropic autosomal recessive disease characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation and premature aging. The molecular basis of A-T is loss of function of the gene encoding A-T-mutated (ATM), a serine/threonine kinase that acts as a master regulator of the DNA damage response, leaving A-T patients highly predisposed to cancers. In addition to its classical role in orchestrating the DNA damage response, recent evidence reports a role for ATM in cellular metabolism, oxidative stress response and insulin signaling. However, it is unclear how defective ATM-dependent response to oxidative stress contributes to A-T clinical manifestations. Here we show that ATM activates glycolysis upon oxidative stress and that its loss leads to impairment of glycolysis and impairment of metabolism in A-T cells. In addition, we identified a metabolic regulator as a major driver of glycolysis impairment and poor cell growth in A-T tissues. Respectively, the downregulation and inactivation of this metabolic regulator in A-T cells restored normal glycolysis, reduced metabolites accumulation and improved A-T cells survival and proliferation. Taken together, our results shed light on a new role of ATM in activating glycolysis and cellular metabolism upon oxidative stress and help to identify a metabolic checkpoint activated in ATM-deficient cells to suppress cellular anabolic pathways and cellular growth. Our study also identified a potential therapeutical target that exerts a synthetic survival effect upon downregulation, to slow down the progression and symptoms of A-T disease.","abstract_has_math":false,"creators":["EL KHAREF, CATIANA"],"institution":"Università degli Studi di Milano","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["tutor: M. Vinciguerra; internal Advidor: K. Havas ; tutor: V. Costanzo ; phd coordinator: S. Minucci","C. 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The molecular basis of A-T is loss of function of the gene encoding A-T-mutated (ATM), a serine/threonine kinase that acts as a master regulator of the DNA damage response, leaving A-T patients highly predisposed to cancers. In addition to its classical role in orchestrating the DNA damage response, recent evidence reports a role for ATM in cellular metabolism, oxidative stress response and insulin signaling. However, it is unclear how defective ATM-dependent response to oxidative stress contributes to A-T clinical manifestations. Here we show that ATM activates glycolysis upon oxidative stress and that its loss leads to impairment of glycolysis and impairment of metabolism in A-T cells. In addition, we identified a metabolic regulator as a major driver of glycolysis impairment and poor cell growth in A-T tissues. Respectively, the downregulation and inactivation of this metabolic regulator in A-T cells restored normal glycolysis, reduced metabolites accumulation and improved A-T cells survival and proliferation. Taken together, our results shed light on a new role of ATM in activating glycolysis and cellular metabolism upon oxidative stress and help to identify a metabolic checkpoint activated in ATM-deficient cells to suppress cellular anabolic pathways and cellular growth. Our study also identified a potential therapeutical target that exerts a synthetic survival effect upon downregulation, to slow down the progression and symptoms of A-T disease."]},{"key":"dc:title","label":"Title","values":["UNDERSTANDING THE MOLECULAR MECHANISM LINKING ATM TO METABOLIC REGULATION."]}]}],"canonical_facts":{"dc:contributor":["tutor: M. Vinciguerra; internal Advidor: K. Havas ; tutor: V. Costanzo ; phd coordinator: S. Minucci","C. 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Here we show that ATM activates glycolysis upon oxidative stress and that its loss leads to impairment of glycolysis and impairment of metabolism in A-T cells. In addition, we identified a metabolic regulator as a major driver of glycolysis impairment and poor cell growth in A-T tissues. Respectively, the downregulation and inactivation of this metabolic regulator in A-T cells restored normal glycolysis, reduced metabolites accumulation and improved A-T cells survival and proliferation. Taken together, our results shed light on a new role of ATM in activating glycolysis and cellular metabolism upon oxidative stress and help to identify a metabolic checkpoint activated in ATM-deficient cells to suppress cellular anabolic pathways and cellular growth. Our study also identified a potential therapeutical target that exerts a synthetic survival effect upon downregulation, to slow down the progression and symptoms of A-T disease."],"dc:identifier":["https://hdl.handle.net/2434/959076","http://dx.doi.org/10.13130/el-kharef-catiana_phd2023-04-13","10.13130/el-kharef-catiana_phd2023-04-13"],"dc:language":["eng"],"dc:publisher":["Università degli Studi di Milano"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:subject":["Ataxia Telangiectasia","Rare disease","Metabolic Disorder","Oxidative Stre","Neurodegeneration","Settore BIO/10 - Biochimica"],"dc:title":["UNDERSTANDING THE MOLECULAR MECHANISM LINKING ATM TO METABOLIC REGULATION."],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-27T20:18:46Z"}