Model of CHD4 enhancement of genotoxic agent-induced apoptosis through DSB repair inhibition and chromatin relaxation. In AML blasts, depletion of CHD4 relaxes the chromatin, resulting in the activation of ATM through Tip60 and thereby primes the cells for apoptotic signaling. Moreover, the relaxed chromatin is more susceptible to genotoxic agent-induced DSBs. Additionally, CHD4-deficient blasts have impaired DSB repair, resulting in the accumulation of more DSBs and further activation of ATM through the classical Mre11, Rad50, NBs1 (MRN) complex. The net activation of ATM in CHD4-depleted cells increases its downstream proapoptotic signaling cascade, thereby resulting in apoptotic cell death.