ATM protein kinase: the linchpin of cellular defenses to stress

Abstract

ATM is the most significant molecule involved in monitoring the genomic integrity of the cell. Any damage done to DNA relentlessly challenges the cellular machinery involved in recognition, processing and repair of these insults. ATM kinase is activated early to detect and signal lesions in DNA, arrest the cell cycle, establish DNA repair signaling and faithfully restore the damaged chromatin. ATM activation plays an important role as a barrier to tumorigenesis, metabolic syndrome and neurodegeneration. Therefore, studies of ATM-dependent DNA damage signaling pathways hold promise for treatment of a variety of debilitating diseases through the development of new therapeutics capable of modulating cellular responses to stress. In this review, we have tried to untangle the complex web of ATM signaling pathways with the purpose of pinpointing multiple roles of ATM underlying the complex phenotypes observed in AT patients.

Tumor protein D52 represents a negative regulator of ATM protein levels

“…Ectopic expression of TPD52 downregulated ATMmediated DNA repair signaling Since γH2AX foci are early markers of DSB sites undergoing DNA damage repair, 4,6 and the rate of γH2AX clearance represents an important factor associated with radiosensitivity, 27 we examined the effects of HA-TPD52 transfection on γH2AX focus formation. In vector-transfected SK-BR-3 cells, the intensity ( Fig.…”

“…In response to DSBs, activation of ATM (ataxia telangiectasia mutated) protein, a member of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family, plays a central role in the recognition and signaling of DNA damage through rapid phosphorylation of numerous substrates. 3,4 The hallmark of ATM's response to DSBs is a rapid increase in kinase activity initiated by autophosphorylation on S 1981 immediately following DSB formation. 5 The rapid phosphorylation of S 139 on H2AX by ATM is essential for focus formation at DNA DSB sites and for further recruitment of repair factors, such as the MRE11-RAD50-NBN (MRN) complex, RAD51, and BRCA1.…”

“…TPD52 detectably bound ATM on fragments aa 1-247 and aa 772-1102, which have been identified as an N-terminal substrate-binding site interacting with substrates such as NBN, p53, and BRCA1, 4 and a binding site (aa 811-950) with β-adaptin, a component of the AP-2 adaptor complex involved in clathrinmediated endocytosis of receptors, 55 respectively. Interaction domain mapping also indicated that the fragment aa 111-131 in TPD52 but not the coiled-coil motif, was essential for TPD52 and ATM binding.…”

Molecular Bases of Ataxia Telangiectasia: One Kinase Multiple Functions

“…An exhaustive picture of the signalling cascades through which ATM modulates cell cycle, cell death and DNA repair is beyond the scope of this chapter and it is available in these suggested reviews [9,[11][12][13].…”

Oxygen sensing is impaired in ATM-defective cells

“…[17][18][19] Besides the progressive cerebellar neurodegeneration that leads to poor coordination, ataxia and the presence of dilated blood vessel, telangiectasia, this syndrome is characterized by increased risk of developing tumors with particular respect to lymphomas and leukemia. Additional abnormalities include immunodeficiency, chromosomal instability, thymic hypoplasia, radiosensitivity and insulin-resistant diabetes.…”