Non-homologous end joining
[6] NHEJ implementations are understood to have been existent throughout nearly all biological systems and it is the predominant double-strand break repair pathway in mammalian cells.
[7] In budding yeast (Saccharomyces cerevisiae), however, homologous recombination dominates when the organism is grown under common laboratory conditions.
Many species of bacteria, including Escherichia coli, lack an end joining pathway and thus rely completely on homologous recombination to repair double-strand breaks.
[9][10] Bacteria utilize a remarkably compact version of NHEJ in which all of the required activities are contained in only two proteins: a Ku homodimer and the multifunctional ligase/polymerase/nuclease LigD.
[11] In mycobacteria, NHEJ is much more error prone than in yeast, with bases often added to and deleted from the ends of double-strand breaks during repair.
[10] Many of the bacteria that possess NHEJ proteins spend a significant portion of their life cycle in a stationary haploid phase, in which a template for recombination is not available.
[12] The archaeal NHEJ system in Methanocella paludicola have a homodimeric Ku, but the three functions of LigD are broken up into three single-domain proteins sharing an operon.
[13] NHEJ has been lost and acquired multiple times in bacteria and archaea, with a significant amount of horizontal gene transfer shuffling the system around taxa.
[14] Corndog and Omega, two related mycobacteriophages of Mycobacterium smegmatis, also encode Ku homologs and exploit the NHEJ pathway to recircularize their genomes during infection.
[15] Unlike homologous recombination, which has been studied extensively in bacteria, NHEJ was originally discovered in eukaryotes and was only identified in prokaryotes in the past decade.
In contrast to bacteria, NHEJ in eukaryotes utilizes a number of proteins, which participate in the following steps: In yeast, the Mre11-Rad50-Xrs2 (MRX) complex is recruited to DSBs early and is thought to promote bridging of the DNA ends.
[16] The corresponding mammalian complex of Mre11-Rad50-Nbs1 (MRN) is also involved in NHEJ, but it may function at multiple steps in the pathway beyond simply holding the ends in proximity.
[32] NHEJ plays a critical role in V(D)J recombination, the process by which B-cell and T-cell receptor diversity is generated in the vertebrate immune system.
[21] A specialized DNA polymerase called terminal deoxynucleotidyl transferase (TdT), which is only expressed in lymph tissue, adds nontemplated nucleotides to the ends before the break is joined.
Loss of capping proteins causes telomere shortening and inappropriate joining by NHEJ, producing dicentric chromosomes which are then pulled apart during mitosis.
These syndromes share many features including cellular radiosensitivity, microcephaly and severe combined immunodeficiency (SCID) due to defective V(D)J recombination.
In contrast, mice lacking Ku or DNA-PKcs are viable, probably because low levels of end joining can still occur in the absence of these components.
Reduced capability for NHEJ can lead to an increase in the number of unrepaired or faultily repaired DNA double-strand breaks that may then contribute to aging.
