Our findings that (i) INO80 counteracts genotoxic R-loops to promotes proliferation of prostate, breast and melanoma cancer cells (Fig. 8), and (ii) INO80 depletion is synthetically lethal with Rad52/APE1 inhibition suggest a chromatin-based R-loop resolution mechanism in cancer cells that suppresses their inherent predisposition for DNA damage during S-phase. The gene discussed is APEX1; the disease is cancer.