The protein kinase ataxia-telangiectasia mutated (ATM) is best known for its role as an apical activator of the DNA damage response in the face of DNA double-strand breaks (DSBs). Following induction of DSBs, ATM mobilizes one of the most extensive signalling networks that responds to specific stimuli and modifies directly or indirectly a broad range of targets.
An Overview of ATM
The ataxia telangiectasia mutated (ATM) protein, a member of the phosphatidylinositol-3-kinase related kinase family (PIKK), is a DNA damage sensor. ATM transmits the DNA damage signal to the downstream repair protein, thus initiating a series of events, such as DNA repair, cell cycle arrest and cell apoptosis, thus maintaining the integrity of the cell genome. It is revealed that ATM is involved in the process of somatic reprogramming. When ATM is completely absent, it significantly affects the acquisition of induced pluripotent stem cells and the stability of chromatin. It also regulates somatic reprogramming by participating in chromatin remodeling in the process of reprogramming. ATM kinase activates different effector substrates and plays the role of cell cycle regulation of DNA repair and cell apoptosis.
Inhibition of ATM
Many inhibitors of ATM have been developed, including KU-55933, KU-60019 and AZD1390. KU-55933 (ATM Kinase Inhibitor) is an effective and specific ATM inhibitor. IC50/Ki is 12.9 nM/2.2 nM in acellular test; KU-60019 is an improved KU-55933 analogue whose IC50 is 6. 3 nM, KU-60019 is also a highly effective radiosensitizer; AZD1390 is a first-in-class orally available and CNS penetrant ATM inhibitor with an IC50 of 0.78 nM in cells and >10,000-fold selectivity over closely related members of the PIKK family of enzymes and excellent selectivity across a broad panel of kinases.
ATM and diseases
ATM kinase mediates tumor cell apoptosis by regulating the interaction between DNA damage and death receptor signaling. The vast majority of tumors are caused by the interaction of genes and environmental factors, and are the result of multifactorial coordination. As a DNA damage repair gene, ATM gene has a mutation in germ cells, and the probability of secondary attack of its allele in somatic cells will increase obviously, which leads to the risk of lymphoma, leukemia, gastric cancer, ovarian cancer and other epithelial tumors. The change of ATM protein expression or activity is involved in the occurrence of many kinds of tumors and affects the treatment and prognosis.