Mechanism and regulation of human non-homologous DNA end-joining

Key Points In multicellular eukaryotes, non-homologous DNA end-joining (NHEJ) is the primary pathway for repairing double-stranded DNA breaks (DSBs). The other important pathway for the repair of such breaks is homologous recombination, which is restricted to late S and G2 phases in dividing cells. Pathological DSBs result when there is replication across a nick, when ionizing radiation passes near the DNA, and when reactive-oxygen species contact DNA. Such breaks are repaired by NHEJ when they occur in G0, G1 or early S phases of the cell cycle, and often even during late S and G2 phases. Physiological DSBs result during V ( D ) J recombination and class-switch recombination. The rejoining phase of these two processes uses NHEJ. NHEJ is typically imprecise in multicellular eukaryotes, making it the only main DNA-repair pathway that is error prone. Because of its error-prone nature, NHEJ might contribute to cancer and ageing. Defects in NHEJ result in sensitivity to ionizing radiation and in a lack of lymphocytes. The lack of lymphocytes results from the loss of the ability to complete V ( D ) J recombination. In humans, mutations in Artemis are responsible for about 15% of cases of severe combined immune deficiency syndrome. Artemis, in complex with the DNA-dependent protein kinase catalytic subunit (DNA-PK cs ), is responsible for trimming the DNA ends in NHEJ. Non-homologous DNA end-joining (NHEJ) — the main pathway for repairing double-stranded DNA breaks — functions throughout the cell cycle to repair such lesions. Defects in NHEJ result in marked sensitivity to ionizing radiation and ablation of lymphocytes, which rely on NHEJ to complete the rearrangement of antigen-receptor genes. NHEJ is typically imprecise, a characteristic that is useful for immune diversification in lymphocytes, but which might also contribute to some of the genetic changes that underlie cancer and ageing.