In this study we extend the earlier observation and demonstrate that enhanced RAD54-BLM functional interaction resulted in increased ability to repair the DNA lesion, thereby decreasing the load of residual cellular damage, which ultimately resulted in enhanced proliferation culminating in chemoresistance in colon cancer cells toward multiple genotoxic agents, as seen in both cellular and preclinical models. Here, ATRX is linked to malignant colon neoplasm.