The ATM protein kinase is well-established as a central signaling molecule in modulating cellular responses to DNA breakage. Patients with mutated ATM genes have a devastating clinical disorder, Ataxia-telangiectasia, with a variety of medical problems, including neurodegeneration, immunodeficiency, cancer predisposition, insulin resistance, and telangiectasia development. Recent data from our lab and others have demonstrated that the ATM protein kinase is also a critical mediator of mitochondrial function and metabolic signaling. Though a significant sensitivity of ATM-defective cells to ionizing irradiation is well-established, a major and unexpected discovery made during the recent funding period of this grant was that ATM-deficient cells are also profoundly sensitive to metabolic stress, notably to depletion of the essential nutrient glucose. The discovery of the extreme sensitivity of ATM-deficient cells to glucose deficiency provides a novel and important tool to study the roles of ATM in metabolic signaling. It is noted that implication of ATM in these stress responses is a significant departure from general concepts about ATM and A-T, but clarifications of these unexpected roles of ATM in metabolic signaling could have impact on general understanding of many disease processes, including those contributing to neurodegenerative disorders, like Parkinson's disease, and to metabolic abnormalities, like type-2 diabetes and metabolic syndrome. Preliminary data is presented demonstrating the profound sensitivity of ATM-deficient cells to glucose deprivation, an activation of the ATM kinase by glucose limitation, documentation of a series of basal and adaptive metabolic abnormalities in A-T cells, and some unexpected interventions which rescue the metabolic sensitivity of A-T cells, such as 2-deoxyglucose treatment, excess glutamine, and reactive metal chelation. The former two rescue approaches point to alterations in NADPH regulation as a central mediator of A-T cell metabolic sensitivity. Using this model system, we also identified a new substrate of the ATM kinase that appears to be involved in this metabolic regulation. Experiments are proposed to further explore the biochemical and molecular roles of ATM in regulating mitochondrial function and metabolic signaling mechanisms. Successful completion of the proposed experiments could lead to new insights into these unexpected cellular functions of the ATM protein and establish new paradigms for common mechanisms that contribute to cancer development, neurodegeneration, and metabolic abnormalities in A-T and other disorders. It is intriguing that one gene product seems to be at a nexus of both DNA damage signaling and metabolic signaling, but perhaps it should not be surprising that these regulation of nucleotide metabolism and DNA damage signaling would be linked in some way, in this case, by ATM. Such insights could enable novel approaches to modulation of these pathways, which can could both enhance research studies and have the potential to lead to development of new therapeutic approaches to treat A-T and other common diseases.

Public Health Relevance

(relevance statement): Ataxia-telangiectasia is a devastating clinical disorder characterized by cerebellar neurodegeneration, cancer predisposition, lung disease, immune deficiency, insulin resistance, and sterility. While the gene mutated in the disease, ATM, plays an unquestionable and critical role in DNA damage signaling, our preliminary data demonstrate an additional central role of the ATM protein kinase in metabolic stress signaling. We believe that these metabolic roles of ATM are important contributors to the devastating clinical phenotypes associated with ATM deficiency, such as the neurodegeneration and cancer, and propose experiments that explore the molecular and biochemical roles of ATM in mitochondrial function and metabolic signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA157216-07A1
Application #
9173446
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Espey, Michael G
Project Start
2011-01-01
Project End
2021-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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