The dynamic interplay in polycomb group (PcG) and trithorax group (TrxG) proteins in response to DNA damage directly involves in the DNA double strand breaks (DSBs) sites and potentially function in both homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways. The process includes chromatin remodeling that is a major mechanism used by cells to relax chromatin in DNA damage response (DDR) and repair. PcGs show resistance ability to the process while, some tumor suppressor genes involves in the DDR and repair by interacting with TrxGs. Understanding how the dynamic interplay in PcGs and TrxGs impacts on DDR will shed light on the mechanisms of carcinogenesis and develop a new target from anti-DDR related drugs.