Mechanism of Double-Strand Break Repair by Non-Homologous End Joining

This chapter highlights progress in understanding the mechanism and regulation of non-homologous end joining (NHEJ) in mammalian cells. Defective NHEJ results in hypersensitivity to DNA-damaging agents, impaired development of lymphocytes and neurons, and predisposition to tumours. Mammalian cells possess several distinct double-strand breaks (DSB) repair pathways, most DSBs are repaired, via a pathway termed NHEJ. Classical end joining (c-NHEJ) is responsible for the bulk of all NHEJ actions in mammalian cells, with the rest being achieved through microhomology dependent alt-NHEJ. To resolve DSBs, NHEJ employs a set of specialised proteins termed NHEJ core factors that function by sensing DSBs, aligning broken DNA ends and acting as a scaffold for a variety of end cleaning/processing enzymes. The concerted action of these proteins results in the generation of ligatable DNA ends and sealing of the damage. Such blocked DNA ends are generated by both ionising radiation and the abortive action of Topo1.