Abstract
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.
Highlights
Ataxia-Telangiectasia Mutated (ATM)Ataxia-telangiectasia mutated is a serine/threonine kinase that is recruited to sites of DNA doublestrand breaks and signals to various downstream targets to initiate cell cycle arrest and DNA repair [1]
AKT is a well-known serine/threonine kinase that is activated by phosphatidylinositol-3-kinase (PI3K) and regulates many cellular processes related to cancer, including survival, cellular metabolism, and DNA repair [74, 75]
Pharmacological inhibition of ATM inhibits AKT phosphorylation and survival in multiple cancer types [82,83,84]. These findings suggest a vital role for AKT in the maintenance of genome integrity, and inhibition of this DNA repair function may result in accumulation of DNA damage and cell death
Summary
Ataxia-telangiectasia mutated is a serine/threonine kinase that is recruited to sites of DNA doublestrand breaks and signals to various downstream targets to initiate cell cycle arrest and DNA repair [1]. ATM has a leucine zipper domain, which is important for its kinase function but not required for dimerization [9]. Active ATM is recruited to the damage site, where it phosphorylates downstream targets including SMC1, Nbs, Chk, BRCA1, and histone H2AX [13, 14]. Patients are predisposed to breast cancer, pancreatic cancer, and melanoma [23]. Low NAD+ and SIRT1 levels are observed in rat models of A-T [29] These observations lead to the investigation of the role of ATM in metabolism
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