Our results demonstrate that AP4 suppresses DNA damage, which occurs spontaneously or at an increased rate after c-MYC activation in CRC cells, by promoting the expression of MDC1. By forming a coherent feed-forward loop, in which AP4 directly induces MDC1 and represses miR-22-3p, a known inhibitor of MDC1, AP4 can exert a tight and robust regulation of MDC1 expression. Here, MDC1 is linked to colorectal carcinoma.