Abstract
DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage because they can result in the loss of large chromosomal regions. In all mammalian cells, DSBs that occur throughout the cell cycle are repaired predominantly by the non-homologous DNA end joining (NHEJ) pathway. Defects in NHEJ result in sensitivity to ionizing radiation and the ablation of lymphocytes. The NHEJ pathway utilizes proteins that recognize, resect, polymerize and ligate the DNA ends in a flexible manner. This flexibility permits NHEJ to function on a wide range of DNA-end configurations, with the resulting repaired DNA junctions often containing mutations. In this Review, we discuss the most recent findings regarding the relative involvement of the different NHEJ proteins in the repair of various DNA-end configurations. We also discuss the shunting of DNA-end repair to the auxiliary pathways of alternative end joining (a-EJ) or single-strand annealing (SSA) and the relevance of these different pathways to human disease.
Highlights
DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage because they can result in the loss of large chromosomal regions
In nonhomologous DNA end joining (NHEJ), the DSB is first recognized by the Ku70–Ku80 hetero dimer (Ku), which acts as a ‘tool belt’ or loading protein to which other non-homologous DNA end joining (NHEJ) proteins can be recruited as needed to promote the joining of DNA ends
We discuss how NHEJ relates to the other pathways of DSB repair, alternative end joining (a-EJ) and single-strand annealing (SSA), and we discuss how NHEJ, a-EJ and SSA contribute to human disease
Summary
DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage because they can result in the loss of large chromosomal regions. The addition of DNA-PKcs, Artemis and Pol μ does not further stimulate ligation, suggesting that the direct ligation of blunt ends is preferred over their processing The ligation of incompatible overhangs is strongly stimulated by the presence of the Artemis–DNA-PKcs complex, which is probably recruited to the DNA end only when resection is required.
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