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. 2021 May 30;12(6):845. doi: 10.3390/genes12060845

Figure 2.

Figure 2

ATM canonical signaling pathway in DNA damage repair, cell cycle arrest and apoptosis. In normal situations, ATM are often inert and form homodimers or polymers. However, when DNA damage occurs, ATM is quickly activated and disassociates into highly active monomers. ATM initiates the DNA-damage response through co-signaling with the MRN (Mre11/Rad50/NBS1) complex at the DNA lesion sites. In fact, direct interaction with the MRN complex induces ATM to phosphorylate a number of downstream targets that are essential for DNA damage repair, cell cycle checkpoint, cell cycle arrest, and apoptosis. During this process, ATM undergoes a series of autophosphorylation on Ser367, Ser1893, Ser1981, and Ser2996 as well as acetylation on Lys3016. Activated ATM is recruited to the DNA damage sites for starting the DNA-damage response. ATM activates BRCA1 and ATF2 to promote cascades of DNA damage repair signaling pathways that involve hundreds of sensors, transducers, and effectors. In addition, ATM also turns on and stabilizes p53 via direct phosphorylation. ATM additionally phosphorylates MDMX to induce its degradation, thereby further stabilizing p53. To its turn, p53 translocates into the nucleus to transactivate a series of its downstream tumor suppressor target genes. For instance, p53 enhances the expression of p21, a potent cyclin-dependent kinase inhibitor. p21 associates with cyclin E, CDK2, CDK4/6 and induces G1/S and G2/M cell cycle arrest, which is critical to prevent unrepaired DNA mutations from passing into daughter cells. p53 also directly transactivates Bid, Bax, PUMA to induce apoptosis when DNA damage is too severe for effective repair. This programmed cell death is a major mechanism of tumor suppression. Moreover, ATM activates RAD9A to further promote cell cycle checkpoints. CHK1 and CHK2 are additionally induced by ATM through phosphorylation. CHK1 subsequently inhibits TLK1 while CHK2 turns on the cell cycle inhibitor CDC25A to block CDK2. As a result, cell cycle progression is temporarily halted to enable DNA damage repair. Thus, thanks to its central role in coordinating DNA damage repair, cell cycle arrest, cell cycle checkpoint, and apoptosis, ATM is frequently considered a major tumor suppressor whose mutations often lead to significant increase in risk of cancer.