DNA double-strand break repair pathway choice: the fork in the road

Abstract

DNA double-strand breaks (DSBs) are cytotoxic lesions that will lead to genomic instability or even tumorigenesis if left unrepaired or misrepaired. To maintain homeostasis, cells have evolved two major repair pathways to counteract DSBs: classical non-homologous end joining (c-NHEJ) and homologous recombination (HR). Two other modes for repairing DSBs have been described: alternative non-homologous end joining (alt-NHEJ) and single-strand annealing (SSA). c-NHEJ ligates adjacent DSB ends directly with rapid kinetics throughout interphase, while HR meticulously initiates DNA-end resection in late S or G2 phase when sister chromatids are available as repair templates. Although partially sharing the DNA-end resection procedure with HR, alt-NHEJ and SSA often contribute to chromosomal translocation and genome rearrangement. Selection of the appropriate pathway to repair DSBs helps to maintain genome integrity. Here, we review current knowledge of the mechanisms regulating DSB repair pathway choice.