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Many cancer therapies, including radiotherapy, induce DSBs as the major driving mechanism for inducing cancer cell death. Thus, modulating DSB repair has immense potential for radiosensitization, although such interventions must be carefully designed to be tumor selective to ensure that normal tissue toxicities are not also increased. Here, we review mechanisms of error-prone DSB repair through a highly efficient process called end joining. There are two major pathways of end-joining repair non-homologous end joining (NHEJ) and alternat