UNDERSTANDING THE MOLECULAR MECHANISM LINKING ATM TO METABOLIC REGULATION.

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.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2023

Author dc:creator

• EL KHAREF, CATIANA

Contributors dc:contributor

• tutor: M. Vinciguerra; internal Advidor: K. Havas ; tutor: V. Costanzo ; phd coordinator: S. Minucci
• C. EL KHAREF
• COSTANZO, VINCENZO
• MINUCCI, SAVERIO

• Ataxia Telangiectasia
• Rare disease
• Metabolic Disorder
• Oxidative Stre
• Neurodegeneration
• Settore BIO/10 - Biochimica

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/el-kharef-catiana_phd2023-04-13
10.13130/el-kharef-catiana_phd2023-04-13

OAI identifier oai:identifier

oai:air.unimi.it:2434/959076