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

Abstract

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.

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…It was thought that because hairpins are not generated in CSR, Artemis does not play a role in this process 24. Therefore the role of the DNA–PK complex in CSR was considered to be in regulating end processing, possibly by phosphorylating other proteins 25. However, it has since been shown that Artemis is indeed involved in CSR, where its nuclease activity may function in resolving more complex lesions that are generated during CSR 26.…”

DNA structures at chromosomal translocation sites

“…(6,7) RAG-1 and RAG-2 proteins act in concert to assemble an appropriate pair of RSSs into a synaptic complex and introduce double-strand breaks (DSBs). (16)(17)(18)(19)(20)(21)(22)(23) The induced DSBs are then repaired by nonhomologous DNA end joining with addition or deletion of nucleotides. (19,24) Recent studies have shown that the LMO-2, Ttg1, Tal1(SCL1), Tal2 (SIL), MTS1 fragile sites represent unintended or cryptic sites (pseudo-signals is another term for these), which the RAGs treat as normal RSS sequences because their sequence is quite close to that of an RSS.…”

“…(16)(17)(18)(19)(20)(21)(22)(23) The induced DSBs are then repaired by nonhomologous DNA end joining with addition or deletion of nucleotides. (19,24) Recent studies have shown that the LMO-2, Ttg1, Tal1(SCL1), Tal2 (SIL), MTS1 fragile sites represent unintended or cryptic sites (pseudo-signals is another term for these), which the RAGs treat as normal RSS sequences because their sequence is quite close to that of an RSS. (25)(26)(27)(28) This misrecognition of the target sequence leads to these translocations or deletions.…”

“…(18)(19)(20)(21)(22)(23) The hairpin is then opened by the Artemis-DNAPKcs complex. (19,75) During non-B DNA structure cleavage, the chemistry is similar and events are simpler. The initial nick is generated by water hydrolysis of phosphodiester bonds close to the non-B DNA structures at the double-stranded DNA region (Fig.…”

DNA double-strand break repair and development

“…In contrast to HR, NHEJ is an error-prone DSB repair mechanism, that involves the DNA-dependent protein kinase (DNA-PK) and the DNA ligase IV (Lig4) complex, which together facilitate re-joining of broken non-compatible DNA ends (Lieber et al, 2003). The DNA-PK complex contains Ku70 and Ku80 proteins, which recognize the break and mediate recruitment of the DNA-PK catalytic subunit, a protein kinase required for efficient NHEJ (Lees-Miller and Meek, 2003;Bassing and Alt, 2004;Burma and Chen, 2004).…”