Non-homologous end joining as a mechanism of DNA repair

In spite of its essential role as the carrier of genetic information, DNA is not an inert structure. The genome is susceptible to potentially mutagenic threats of both endogenous and environmental origin. A dramatic threat to the covalent structure of DNA is posed by breaks in the phosphate backbone affecting one or both strands of the Watson–Crick double helix. Ionizing radiation and certain chemotherapeutic drugs, for example, generate single-strand and, less commonly, double-strand breaks, as well as clustered base lesions in both DNA strands where simultaneous excision-repair has the potential to convert a single-strand to a double-strand break. The cell is not unduly troubled by single-strand breaks, as it sees these as reaction intermediates during the excision-repair of DNA base damage, and so deals with them accordingly. However, a double-strand break is an extremely dangerous lesion, posing one of the greatest threats not just to the informational integrity but also to the structural cohesion of the DNA. Unless quickly repaired, such breaks can lead to chromosomal deletion, loss, rearrangement or cytotoxicity if the cell continues its cycle of DNA replication and cell division. Not surprisingly, numerous proteins are involved in detecting and repairing DNA double-strand breaks, or checking cell-cycle progression until repair is complete. Double-strand break repair mechanisms rely on enzymes which evolved primarily to deal with developmentally programmed double-strand breaks. The deliberate targeted introduction of DNA double-strand breaks by endonucleases and their coordinated repair underpin key biological processes such as recombination between homologous chromosomes during meiosis or V(D)J rearrangements of immunoglobulin and T-cell receptor genes. The two main repair mechanisms that the cell can use when faced with an accidentally introduced DNA double-strand break, homologous recombination and non-homologous end joining, largely recruit those enzymes involved ordinarily in meiotic and V(D)J recombination, respectively. The strategy of homologous recombination relies on the fact that replication generates an identical copy of the cellular DNA and the undamaged copy can be used as a template for resynthesis and repair of a damaged DNA strand. In this mode, homologous recombination is restricted to the S phase of the cell cycle, and serves to restart the replication machinery by resolving unfavourable DNA structures generated when a replication fork stalls. Homologous recombination requires extensive stretches of DNA sequence homology but is then a very accurate method of repair. By contrast, non-homologous end joining is a much more robust but low fidelity form of double-strand break repair, …