In 1995, the gene was discovered by Yosef Shiloh[6] who named its product ATM since he found that its mutations are responsible for the disorderataxia–telangiectasia.[7] In 1998, the Shiloh andKastan laboratories independently showed that ATM is a protein kinase whose activity is enhanced by DNA damage.[8][9]
Throughout thecell cycle DNA is monitored for damage. Damages result from errors duringreplication, by-products of metabolism, general toxic drugs orionizing radiation. The cell cycle has differentDNA damage checkpoints, which inhibit the next or maintain the currentcell cycle step. There are two main checkpoints, the G1/S and the G2/M, during the cell cycle, which preserve correct progression. ATM plays a role in cell cycle delay after DNA damage, especially afterdouble-strand breaks (DSBs).[10] ATM is recruited to sites of double strand breaks by DSB sensor proteins, such as the MRN complex. After being recruited, it phosphorylatesNBS1, along other DSB repair proteins. These modified mediator proteins then amplify the DNA damage signal, and transduce the signals to downstream effectors such asCHK2 andp53.
The ATM gene codes for a 350 kDa protein consisting of 3056 amino acids.[11] ATM belongs to the superfamily ofphosphatidylinositol 3-kinase-related kinases (PIKKs). The PIKK superfamily comprises six Ser/Thr-protein kinases that show a sequence similarity tophosphatidylinositol 3-kinases (PI3Ks). This protein kinase family includesATR (ATM- and RAD3-related),DNA-PKcs (DNA-dependent protein kinase catalytic subunit) andmTOR (mammalian target of rapamycin). Characteristic for ATM are five domains. These are from N-terminus to C-terminus theHEAT repeat domain, the FRAP-ATM-TRRAP (FAT) domain, the kinase domain (KD), the PIKK-regulatory domain (PRD) and the FAT-C-terminal (FATC) domain. The HEAT repeats directly bind to the C-terminus ofNBS1. The FAT domain interacts with ATM's kinase domain to stabilize the C-terminus region of ATM itself. The KD domain resumes kinase activity, while the PRD and the FATC domain regulate it. The structure of ATM has been solved in several publications usingcryo-EM. In the inactive form, the protein forms ahomodimer. In the canonical pathway, ATM is activated by the MRN complex andautophosphorylation, forming active monomers capable of phosphorylating several hundred downstream targets. In the non-canonical pathway, e.g. through simulation by oxidative stress, the dimer can be activated by the formation ofdisulfide bonds.[12] The entire N-terminal domain together with the FAT domain are adopt an α-helical structure, which was initially predicted by sequence analysis. This α-helical structure forms atertiary structure, which has a curved, tubular shape present for example in theHuntingtin protein, which also contains HEAT repeats. FATC is the C-terminal domain with a length of about 30 amino acids. It is highly conserved and consists of anα-helix.[13]. See thedetailed description of ATM gene and related protein domains.
Schematic illustration of the four known conserved domains in four members of the PIKKs family[13]
A complex of the three proteinsMRE11,RAD50 andNBS1 (XRS2 in yeast), called theMRN complex in humans, recruits ATM todouble strand breaks (DSBs) and holds the two ends together. ATM directly interacts with theNBS1 subunit and phosphorylates the histone variantH2AX on Ser139.[14] This phosphorylation generates binding sites for adaptor proteins with aBRCT domain. These adaptor proteins then recruit different factors including the effector protein kinaseCHK2 and the tumor suppressorp53. The ATM-mediated DNA damage response consists of a rapid and a delayed response. The effector kinase CHK2 is phosphorylated and thereby activated by ATM. Activated CHK2 phosphorylates phosphataseCDC25A, which is degraded thereupon and can no longer dephosphorylateCDK1-cyclin B, resulting in cell-cycle arrest. If the DSB can not be repaired during this rapid response, ATM additionally phosphorylatesMDM2 andp53 at Ser15.[9] p53 is also phosphorylated by the effector kinase CHK2. These phosphorylation events lead to stabilization and activation of p53 and subsequent transcription of numerous p53 target genes including CDK inhibitorp21 which lead to long-term cell-cycle arrest or even apoptosis.[15]
ATM-mediated two-step response to DNA double strand breaks. In the rapid response activated ATM phosphorylates effector kinase CHK2 which phosphorylates CDC25A, targeting it for ubiquitination and degradation. Therefore, phosphorylated CDK2-Cyclin accumulates and progression through the cell cycle is blocked. In the delayed response ATM phosphorylates the inhibitor of p53, MDM2, and p53, which is also phosphorylated by Chk2. The resulting activation and stabilization of p53 leads to an increased expression of Cdk inhibitor p21, which further helps to keep Cdk activity low and to maintain long-term cell cycle arrest.[15]
The protein kinase ATM may also be involved in mitochondrial homeostasis, as a regulator of mitochondrial autophagy (mitophagy) whereby old, dysfunctional mitochondria are removed.[16] Increased ATM activity also occurs in viral infection where ATM is activated early during dengue virus infection as part of autophagy induction and ER stress response.[17]
A functionalMRN complex is required for ATM activation after DSBs. The complex functions upstream of ATM in mammalian cells and induces conformational changes that facilitate an increase in the affinity of ATM towards its substrates, such as CHK2 and p53.[10]Inactive ATM is present in the cells without DSBs as dimers or multimers. Upon DNA damage, ATM autophosphorylates on residue Ser1981. This phosphorylation provokes dissociation of ATM dimers, which is followed by the release of active ATM monomers.[18] Further autophosphorylation (of residues Ser367 and Ser1893) is required for normal activity of the ATM kinase. Activation of ATM by theMRN complex is preceded by at least two steps, i.e. recruitment of ATM to DSB ends by the mediator of DNA damage checkpoint protein 1 (MDC1) which binds toMRE11, and the subsequent stimulation of kinase activity with theNBS1 C-terminus.The three domains FAT, PRD and FATC are all involved in regulating the activity of the KD kinase domain. The FAT domain interacts with ATM's KD domain to stabilize the C-terminus region of ATM itself. The FATC domain is critical for kinase activity and highly sensitive to mutagenesis. It mediates protein-protein interaction for example with the histoneacetyltransferase TIP60 (HIV-1 Tat interacting protein 60 kDa), which acetylates ATM on residue Lys3016. The acetylation occurs in the C-terminal half of the PRD domain and is required for ATM kinase activation and for its conversion into monomers. While deletion of the entire PRD domain abolishes the kinase activity of ATM, specific small deletions show no effect.[13]
People who carry aheterozygous ATM mutation have increased risk of mainlypancreatic cancer,prostate cancer,stomach cancer andinvasive ductal carcinoma of the breast.[19] Homozygous ATM mutation confers the diseaseataxia–telangiectasia (AT), a rare human disease characterized by cerebellar degeneration, extreme cellular sensitivity to radiation and a predisposition to cancer. All AT patients contain mutations in the ATM gene. Most other AT-like disorders are defective in genes encoding theMRN protein complex. One feature of the ATM protein is its rapid increase in kinase activity immediately following double-strand break formation.[20][8] The phenotypic manifestation of AT is due to the broad range of substrates for the ATM kinase, involving DNA repair,apoptosis, G1/S, intra-S checkpoint and G2/M checkpoints, gene regulation,translationinitiation, andtelomere maintenance.[21] Therefore, a defect in ATM has severe consequences in repairing certain types of damage to DNA, andcancer may result from improper repair. AT patients have an increased risk for breast cancer that has been ascribed to ATM's interaction and phosphorylation ofBRCA1 and its associated proteins following DNA damage.[22]
Mutations in the ATM gene are found at relatively low frequencies in sporadic cancers. According toCOSMIC, theCatalogue Of Somatic Mutations In Cancer, the frequencies with which heterozygous mutations in ATM are found in common cancers include 0.7% in 713 ovarian cancers, 0.9% in central nervous system cancers, 1.9% in 1,120 breast cancers, 2.1% in 847 kidney cancers, 4.6% in colon cancers, 7.2% among 1,040 lung cancers and 11.1% in 1790 hematopoietic and lymphoid tissue cancers.[23] Certain kinds ofleukemias andlymphomas, includingmantle cell lymphoma,T-ALL, atypicalB cell chronic lymphocytic leukemia, andT-PLL are also associated with ATM defects.[24] A comprehensive literature search on ATM deficiency in pancreatic cancer, that captured 5,234 patients, estimated that the total prevalence of germline or somatic ATM mutations in pancreatic cancer was 6.4%.[25] ATM mutations may serve as predictive biomarkers of response for certain therapies, since preclinical studies have found that ATM deficiency can sensitise some cancer types toATR inhibition.[26][27][28][29]
Frequent epigenetic deficiencies of ATM in cancers
ATM is one of the DNA repair genes frequentlyhypermethylated in its promoter region in various cancers (see table of such genes inCancer epigenetics). The promoter methylation of ATM causes reduced protein ormRNA expression of ATM.
More than 73% of brain tumors were found to be methylated in the ATM gene promoter and there was strong inverse correlation between ATM promoter methylation and its protein expression (p < 0.001).[30]
The ATM gene promoter was observed to be hypermethylated in 53% of small (impalpable) breast cancers[31] and was hypermethylated in 78% of stage II or greater breast cancers with a highly significant correlation (P = 0.0006) between reduced ATM mRNA abundance and aberrant methylation of the ATM gene promoter.[32]
In non-small cell lung cancer (NSCLC), the ATM promoter methylation status of paired tumors and surrounding histologically uninvolved lung tissue was found to be 69% and 59%, respectively. However, in more advanced NSCLC the frequency of ATM promoter methylation was lower at 22%.[33] The finding of ATM promoter methylation in surrounding histologically uninvolved lung tissue suggests that ATM deficiency may be present early in afield defect leading to progression to NSCLC.
In squamous cell carcinoma of the head and neck, 42% of tumors displayed ATM promoter methylation.[34]
DNA damage appears to be the primary underlying cause of cancer,[35] and deficiencies in DNA repair likely underlie many forms of cancer.[36] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increasemutational errors duringDNA replication due to error-pronetranslesion synthesis. Excess DNA damage may also increaseepigenetic alterations due to errors during DNA repair.[37][38] Such mutations and epigenetic alterations may give rise to cancer. The frequent epigenetic deficiency of ATM in a number of cancers likely contributed to the progression of those cancers.
ATM functions duringmeiotic prophase.[39] The wild-type ATM gene is expressed at a four-fold increased level in humantestes compared tosomatic cells (such as skin fibroblasts).[40] In both mice and humans, ATM deficiency results in female and maleinfertility. Deficient ATM expression causes severe meiotic disruption duringprophase I.[41] In addition, impaired ATM-mediated DNA DSB repair has been identified as a likely cause of aging of mouse and human oocytes.[42] Expression of the ATM gene, as well as other key DSB repair genes, declines with age in mouse and human oocytes and this decline is paralleled by an increase of DSBs in primordial follicles.[42] These findings indicate that ATM-mediated homologous recombinational repair is a crucial function of meiosis.
Several ATM kinase inhibitors are currently known, some of which are already in clinical trials.[43][44][45] One of the first discovered ATM inhibitors iscaffeine with an IC50 of 0.2 mM and only a low selectivity within thePIKK family.[46][47]Wortmannin is an irreversible inhibitor of ATM with no selectivity over other related PIKK and PI3K kinases.[48] The most important group of inhibitors are compounds based on the 3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one scaffold. The first important representative is the inhibitor isDactolisib (NVP-BEZ235), which was first published by Novartis as a selective mTOR/PI3K inhibitor.[49] It was later shown to also inhibit other PIKK kinases such as ATM, DNA-PK and ATR.[50] Various optimisation efforts by AstraZeneca (AZD0156,AZD1390), Merck (M4076) and Dimitrov et al. have led to highly active ATM inhibitors with greater potency.[51][52][53]
Caffeine is an ATM inhibitor with low activityAZD0156 is a highly active ATM inhibitor from AstraZeneca
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^Clinical trial numberNCT04882917 for "First-in-human Study of M4076 in Advanced Solid Tumors (DDRiver Solid Tumors 410) " atClinicalTrials.gov
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