Figure 3.

ATM non-canonical signaling pathways. Chromatin alterations induced by chloroquine or hypotonic stress could trigger ATM activation without requiring the MRN complex. The active monomer of ATM interacts with ATMIN (ATM interacting protein) to transduce downstream signaling to CHK2, p53, KAP1, and other substrates to promote genomic integrity and survival. ATM also serves as an important redox sensor. After being activated by ROS or oxidation, ATM homodimers establish disulfide bonds to maintain their dimer conformations. This activation process also does not require the MRN complex. Similar to active ATM monomers, induced ATM dimers are phosphorylated at Ser1981 but this posttranslational modification is not required for phosphorylation of downstream targets such as CHK2 at Thr68 or p53 at Ser18. Oxidation-activated ATM dimers then phosphorylate LKB1 and AMPK to turn on TSC2 and block mTOR signaling, thereby decreasing ROS levels. ATM can also be induced by severe hypoxia in a ROS-independent manner. In severe hypoxia, the function of ribonucleotide reductase is inhibited, causing the depletion of deoxynucleoside triphosphates (dNTPs) as well as replication stress. As a result, ATM and ATR are activated due to severe hypoxia. ATM and ATR then phosphorylate and stabilize HIF1α to enable cell survival under hypoxic conditions.