Double-Strand Break Repair

Abstract

Synopsis DNA double-strand breaks (DSBs) are the most dangerous form of DNA damage and can lead to death, mutation, or malignant transformation. Mammalian cells use three major pathways to repair DSBs: homologous recombination (HR), classical nonhomologous end joining (C-NHEJ), and alternative end joining (A-NHEJ). Cells choose among the pathways by interactions of the pathways with CtIP and 53BP1. HR is restricted to S and G2 phases of the cell cycle, utilizing homologous newly replicated DNA for error-free repair. Inherited mutations in the HR genes BRCA1, BRCA2, and PALB2 cause susceptibility to breast, ovarian, and pancreatic cancer. C-NHEJ operates during all phases of the cell cycle and during V(D)J recombination of the antibody and T-cell receptor genes, joining DNA ends while minimizing nucleotide loss and addition for error-prone repair. Inherited mutations in the C-NHEJ genes DNA-PKcs, Artemis, and XLF cause the syndrome of radiation sensitivity with severe combined immunodeficiency. A-NHEJ is a backup pathway for C-NHEJ, joining DNA ends after resection back to regions of microhomology for error-prone repair. A-NHEJ is responsible for creating the chromosomal translocations seen in cancer. Thus, understanding DSB repair pathways will lead to insights for immunology and cancer.