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ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development

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ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development G C A T T A C G G C A T genes Review ATM: Main Features, Signaling Pathways, and Its Diverse Roles in DNA Damage Response, Tumor Suppression, and Cancer Development Liem Minh Phan 1,* and Abdol-Hossein Rezaeian 2,* 1 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA 2 Department of Drug Discovery & Biomedical Sciences, College of Pharmacy, The University of South Carolina, Columbia, SC 29208, USA * Correspondence: [email protected] (L.M.P.); [email protected] (A.-H.R.) Abstract: ATM is among of the most critical initiators and coordinators of the DNA-damage response. ATM canonical and non-canonical signaling pathways involve hundreds of downstream targets that control many important cellular processes such as DNA damage repair, apoptosis, cell cycle arrest, metabolism, proliferation, oxidative sensing, among others. Of note, ATM is often considered a major tumor suppressor because of its ability to induce apoptosis and cell cycle arrest. However, in some advanced stage tumor cells, ATM signaling is increased and confers remarkable advantages for cancer cell survival, resistance to radiation and chemotherapy, biosynthesis, proliferation, and metastasis. This review focuses on addressing major characteristics, signaling pathways and especially the diverse roles of ATM in cellular homeostasis and cancer development. Citation: Phan, L.M.; Rezaeian, A.-H. ATM: Main Features, Signaling Keywords: ATM; cancer; DNA damage repair; DNA damage response; oxidative sensing; autophagy; Pathways, and Its Diverse Roles in hypoxia; pexophagy; mitophagy; cellular homeostasis DNA Damage Response, Tumor Suppression, and Cancer Development. Genes 2021, 12, 845. https://doi.org/10.3390/ 1. Introduction genes12060845 During the past three decades, the study of ATM (ataxia telangiectasia mutated) has Academic Editors: Junya Kobayashi played a central role in advancing our understanding of the mammalian DNA damage and Qiu-Mei Zhang-Akiyama response, cancer initiation and progression as well as redox signaling pathways. Numer- ous recent publications additionally reported the varied roles and influences of ATM in Received: 3 May 2021 multiple cellular processes, for instance, growth, metabolism, energy production, oxidative Accepted: 27 May 2021 homeostasis, chromatin remodeling, and genomic integrity, which are all important pro- Published: 30 May 2021 cesses in tumor development and progression. Although ATM should be considered as a tumor suppressor because its mutations often lead to cancer, there are mounting evidence Publisher’s Note: MDPI stays neutral showing that ATM’s functions and signaling pathways may also contribute to cancer cells’ with regard to jurisdictional claims in resistance to radiation, chemotherapy, and even assist tumor progression in some scenarios. published maps and institutional affil- In this review, we will cover the major features, roles, and signaling pathways of ATM, iations. especially its diverse roles in tumor suppression and cancer progression. 2. The Structure and Domain Mapping of ATM The ATM gene consists of 66 exons and is located on chromosome 11 (11q22-23) [1]. In Copyright: © 2021 by the authors. its active monomeric form, ATM has a large size of 370 kDa. ATM is an important member Licensee MDPI, Basel, Switzerland. of the PI3K-related protein kinase family (PIKK) [2]. Other members of this family include This article is an open access article DNA-dependent protein kinase catalytic subunit (DNA-PKcs), ataxia-telangiectasia and distributed under the terms and Rad3-related (ATR), mammalian target of rapamycin (mTOR), SMG-1, TRRAP, among conditions of the Creative Commons others [3–5]. Similar to these members, ATM possesses a kinase domain whose structure Attribution (CC BY) license (https:// shares significant homology to that of the phosphatidyl inositol 3 kinase (PI3K). Thanks creativecommons.org/licenses/by/ to this domain, ATM is an active serine/threonine kinase. Besides, ATM also has a FAT 4.0/). Genes 2021, 12, 845. https://doi.org/10.3390/genes12060845 https://www.mdpi.com/journal/genes Genes 2021, 12, x FOR PEER REVIEW 2 of 11 Genes 2021, 12, 845 2 of 11 (PI3K). Thanks to this domain, ATM is an active serine/threonine kinase. Besides, ATM al(FRAPso has (FK506-bindinga FAT (FRAP (FK506 protein-binding 12-rapamycin-associated protein 12-rapamycin protein-associated (mTOR)), protein ATM, (mTOR)), TRAPP A(Transformation/transcriptionTM, TRAPP (Transformation/transcription domain-associated domain protein))-associated domain protein)) and a domain FATC domain and a FATCthat is domain located that on its is C-terminallocated on its [6]. C In-terminal 2006, Jiang [6]. In et al.2006, additionally Jiang et al. showed additionally that the showe FATCd thatdomain the FATC was essential domain for was ATM essential to interact for ATM with to its interact partners with for activation its partners and for control activation of its andkinase control activity of its [7 ].kinase activity [7]. TheThe N N-terminus-terminus of of ATM ATM contains contains multiple multiple αα helicalhelical HEAT HEAT repeat repeat motifs motifs and and a a region region thatthat appear appear to to be be critical critical for for ATM ATM interactions interactions with with other other proteins proteins and and DNA DNA by by serving serving as as scaffolds.scaffolds. It It has has been been shown shown that that HEAT HEAT motifs motifs are are necessary necessary for for ATM ATM to to interact interact with with and and recruitrecruit a a number ofof proteinsproteins to to the the DNA DNA lesion lesion sites sites for for DNA DNA damage damage repair repair [8– 11[8].–11] In. fact, In fact,ATMIN ATMIN (ATM (ATM interacting interacting protein), protein), NBS1 NBS1 (a component (a component of the MRNof the complex), MRN complex), and NKX3.1 and NKX3.1(a prostate (a prostate tumor suppressor)tumor suppressor) have been have found been tofound bind to to bind ATM’s to ATM’s HEAT motifsHEAT [motifs12–15]. [12In– 2004,15]. In Lavin 2004, et Lavin al., also et al., reported also reported the presence the presence of other of motifs, other a motifs, proline-rich a proline area-rich for c-Ablarea forbinding, c-Abl binding, and a leucine and a zipper leucine on zipper ATM [on16 ,ATM17] (Figure [16,17]1). (Figure 1). Figure 1. Human ATM’s domain map. ATM is a large gene with 66 exons and consists of multiple domains that allow its Figure 1. Human ATM’s domain map. ATM is a large gene with 66 exons and consists of multiple domains that allow its proteinprotein to to directly directly interact interact with with numerous numerous regulators, regulators, partners, partners, and and downstream downstream targets. targets. In In its its N N terminus, terminus, ATM ATM contains contains aa Nuclear Nuclear Localization Localization Signal Signal that that enables enables its its nuclear nuclear translocation. translocation. ATM ATM also also uses uses its its N N-terminus-terminus for for interacting interacting wi withth chromatin,chromatin, substrates substrates and and partners, partners, for for instance, instance, p53, p53, LKB1, LKB1, NBS1, NBS1, among among others. others. The The putative putative leucine leucine zipper zipper motif motif on on ATMATM N N-terminus-terminus is documented toto bebe essentialessentialfor for its its dimerization dimerization and and interaction interaction with with other other partners partners or or substrates. substrates. On On its itsC-terminus, C-terminus, ATM ATM has has a FATa FAT (FRAP, (FRAP, ATM ATM and and TRRAP TRRAP proteins) proteins) domain domain which which contains contains autophosphorylation autophosphorylation sites sites and and is iscritical critical for for substrate substrate binding. binding. As As a kinase,a kinase, ATM ATM has has a serine/threoninea serine/threonine kinase kinase domain domain that that is is highly highly homologous homologous to to that that of ofthe the PI3K. PI3K. At At the the end end of of its its C-terminus C-terminus is is the the FATC FATC domain domain that that isis essentialessential forfor ATMATM fullfull activation and interactions interactions with with partners. Of note, ATM contains multiple important autophosphorylation sites that can substantially affect its functions. partners. Of note, ATM contains multiple important autophosphorylation sites that can substantially affect its functions. For instance, Ser367, Ser1893, Ser1981, and Ser2996 are auto-phosphorylated after irradiation. Thr1885 is not induced by For instance, Ser367, Ser1893, Ser1981, and Ser2996 are auto-phosphorylated after irradiation. Thr1885 is not induced by irradiation. In human cells, autophosphorylation on three residues Ser367, Ser1893, Ser1981, and acetylation on Lys3016 haveirradiation. been shown In human to be cells, important autophosphorylation for ATM activation. on three Aurora residues B phosphorylates Ser367, Ser1893, ATM Ser1981, at Ser1403 and acetylation during mitosis. on Lys3016 Im- portantly,have been ATM shown also to be has important 49 α helical for ATM HEAT activation. motifs whose Aurora name B phosphorylates is derived from ATM huntingtin, at Ser1403 duringelongation mitosis. factor Importantly, 3, the A subunitATM also of hasprotein 49 α phosphatasehelical HEAT 2A, motifs and whose target name of rapamycin is derived 1 from(TOR1). huntingtin, These motifs elongation serve factoras scaffolds 3, theA and subunit are critical of protein for ATMphosphatase interactions 2A, andwith target proteins of rapamycinand DNA. 1 (TOR1). These motifs serve as scaffolds and are critical for ATM interactions with proteins and DNA. 3. ATM’s role in DNA Damage Response and Ataxia Telangiectasia ATM is an important initiator of the DNA-damage response in mammalian cells via the Mre11/Rad50/Nbs1 (MRN) complex at the DNA lesion sites [18–21]. ATM activation Genes 2021, 12, 845 3 of 11 Genes 2021, 12, x FOR PEER REVIEW3. ATM’s role in DNA Damage Response and Ataxia Telangiectasia 3 of 11 ATM is an important initiator of the DNA-damage response in mammalian cells via the Mre11/Rad50/Nbs1 (MRN) complex at the DNA lesion sites [18–21].
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