ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors

Abstract

Ataxia-telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.

Keywords: ATM; DNA damage; hereditary tumors; precision therapy; redox homeostasis; tumor profiling.

Figure 1

(a) Map of the ATM protein, consisting of 3056 amino acids. ATM domains and motifs are listed with their amino acid numbers. Chromatin-association domain serves is important in interacting with chromatin or partner proteins. Nuclear Localization Signal enables nuclear translocation of ATM. Lys3016 is acetylated by TIP60. ATM has multiple phosphorylation sites that can substantially affect its kinase function. Ser367, Ser1893, Thr1885, Ser1981, and Ser2996 are auto-phosphorylated sites. Among them, auto-phosphorylation on Ser367, Ser1893, Ser1981, and acetylation on Lys 3016 are important for ATM activation. FATC domain on C-terminus of ATM is essential for its full activation. Cys2991 is essential to form disulfide bond between two ATM monomers. (b) The structure of an ATM closed dimer (PDB ID: 6K9L [23]), created with Jmol, an open-source Java viewer for chemical structures in 3D. (c) A schematic representation of the ATM protein. Interface of ATM homodimer consists of upper (FLAP−FLAP-BE) and lower (M-FAT−M-FAT) layers. In the closed dimer, active site of kinase domain is blocked, leaving ATM in an inactive state. In the open dimer, the upper interface is lost, resulting in more compact dimer and allowing partial access to the active site of the kinase domain. FAT-KIN: FAT-phosphatidylinositol 3-kinase-like kinase domain; FLAP-BE: FLAP-binding element; FLAP: Lst8 binding element (LBE), activation loop, and PIKK-regulatory domain (PRD) region.

Figure 2

ATM signaling pathway in response to DSBs. ATM is recruited to sites of DSBs by the MRN complex. At the DSB site, ATM undergoes activation through acetylation by TIP60 and autophosphorylation. Direct interaction between the ATM and MRN complex is essential for ATM activation and monomerization. Activated ATM then phosphorylate H2AX surrounding the DSBs, which recruits more of the MRN complex to the site and forms a positive feedback loop between the MRN complex and ATM. ATM phosphorylates and activates a number of downstream targets that are essential for DNA damage repair (NHEJ and HR), cell cycle inhibition, and apoptosis. DNA damages are repaired through either NHEJ or HR in context of the cell cycle state.

Figure 3

(a) Chromatin alterations trigger ATM activation through interaction with ATMIN. ATMIN competes with NBS1 in binding to ATM. Activated ATM phosphorylates and activates p53, CHK2, and Kap1 to promote genomic integrity and cell survival. (b) Oxidative stress can also trigger ATM activation through forming intermolecular disulfide bonds in the manner depending on TRX1. Glucose depletion or hypoxia also activate ATM. To reduce oxidative stress or other cellular stress, ATM then activates transcription of genes involved in the antioxidant response. ATM also promotes autophagy and mitophagy to maintain ROS homeostasis while suppressing mTORC1.