The ataxia-telangiectasia (A-T) syndrome is a rare, autosomal recessive disorder caused by the mutations in the ATM gene, characterized by progressive cerebellar ataxia, neuro-degeneration, radiosensitivity, cell-cycle checkpoint defects, genome instability, and a predisposition to cancer. The ATM protein is a serine/threonine protein kinase belonging to the phosphoinositide 3-kinase-related protein kinase (PIKK) family involved in signaling following cellular stress, specifically targeting the ATM consensus phosphorylation motif hydrophobic-X-hydrophobic-[S/T]-Q. The ATM protein has five domains including the N-terminal HEAT repeat domain, the FAT (FRAP-ATM-TRRAP) domain, the protein kinase domain (KD), the PIKK-regulatory domain (PRD), and the C-terminal FAT-C domain. [1]
In normal undamaged cells, the ATM protein exists in an inactive state as dimers. Following induction of DNA damage or treatment with agents that alter chromatin structure, ATM undergoes an intermolecular auto-phosphorylation on S1981, resulting in the disassociation of ATM dimers into active monomers, which is also important for the interaction between ATM and the mediator of DNA damage checkpoint protein 1 (MDC1) to mediate ATM retention at sites of DNA double-strand breaks. PP2A (protein phosphatase 2A) and the WIP1 phosphatase can modulate the phosphorylation levels of ATM and its downstream targets. Additionally, the histone acetyl-transferase TIP60 also acetylates ATM on Lysine 3016 (K3016) for ATM activation. The MRN heterotrimeric complex of Mre11, Rad50 and NBS1 found at the sites of DNA double-strand breaks is also required for the full activation of the ATM-dependent DNA damage response. ATM phosphorylates the histone variant H2AX, producing γH2AX on Serine 139, and the adapter protein MDC1 which binds to γH2AX via its BRCT repeats is also recruited and phosphorylated by ATM. The formation of γH2AX and the phosphorylation of MDC1 at the sites of DNA damage provide a docking station for many components of the DNA damage repair and signaling pathways. [1]
During cell cycle control, ATM is activated to phosphorylate the p53 and MDM2, allowing p53 to trans-activate target genes, particularly the cyclin dependent kinase (CDK) inhibitor p21 which results in the inhibition of the Cyclin-E/CDK2 complex and inhibition of progression from G1 into S-phase. ATM activates CHK2 by phosphorylation on threonine 68 (T68), leading to CHK2-mediated inhibition of the CDC25 family of phosphatases, which is critical to the initiation of DNA replication, as well as the induction of G1/S or G2/M checkpoints. Additionally, ATM targets NBS1 protein of the MRN complex, which is involved in the radiation-induced intra-S-phase arrest. ATM also phosphorylates BRCA1 (Breast Cancer Associated 1) on multiple sites, and these different phosphorylation events elicit different effects on cell cycle progression, with phosphorylation on serine 1387 necessary for proper S-phase arrest following ionizing radiation, and phosphorylation on serine 1423 for the ATM mediated G2/M arrest. ATM mediated phosphorylation of SMC1 and FANCD2 proteins are also important for IR induced S-phase arrest. Furthermore, ATM activity is also required for optimal repair of DNA double-strand breaks, by interacting with the DNA repair enzyme Artemis specifically in G2 to promote DNA repair. [1]
Given the critical role of ATM in DNA repair and the increased radio-sensitivity following inhibition of ATM, blocking of ATM kinase activity by small molecule inhibitors could prove beneficial in the treatment of cancer, which is confirmed by studies that transient ATM inhibition has been shown to be sufficient to increase the sensitivity of cells to ionizing radiation. [1]
