Inhibition of CHD4 activates the ATM signaling pathway to induce increased apoptosis. (A) Depletion of CHD4 in U937 cells induces a significant activation of ATM, which is blocked by the concurrent depletion of Tip60. (B) Upon addition of DNR, ATM is activated in a concentration-dependent manner, with significantly more activation in the CHD4-depleted cells. (C) Once active, ATM acts on its downstream targets, including stabilizing the proapoptotic transcription factor E2F1. E2F1 is stabilized in a DNR concentration-dependent manner, (D) with significantly more being stabilized in the CHD4-depleted cells. (E) This stabilization is diminished upon the addition of the ATM inhibitor KU60019. (F) Ultimately, in response to the DNR, CHD4-depleted AML cells display elevated markers of apoptosis, including PARP and Caspase-3 cleavage.