DNA repair - NHEJ - Canonical Non-homologus end joining pathway 2.0 - Full HD
The DNA damage response (DDR) of the cell includes: (i) sensing, (ii) signalling and (iii) its repair. Double strand breaks (DSBs) are the most toxical DNA damage. They can be produced by ionizing radiation, laser beam, Topoisomerase II enzyme, endonucleases, chemical-clastogenic compounds such as bleomycin, or also they can arise from single-stranded break (SSB) in DNA. Around nine DSB are generated in each cell per day, under physiological conditions(1).
The sensing and signalling of DSBs are very important for the maintenance of the genome and chromosomal stability. The non-homologus end joining (NHEJ) pathway, mostly repairs DSB during the G1 phase of cell cycle, although, also can act in G2(2). It is generally accepted that NHEJ repairs DSB in an error-prone way, but it only happens when the DSB DNA ends are incompatible and therefore must be processed before its repair.
The processing of DNA terminis and microhomology search of incompatible DNA ends are carried out by the "alternative" (A-NHEJ) pathway(3). The A-NHEJ seems to be activated under XRRC1, Ku or DNA PKcs deficient function. When a clean DSB is generated, the canonical NHEJ pathway (C-NHEJ), also called direct NHEJ repair pathway, is in charge to repair them(4; 5) in a highly efficient fashion.
Main steps of C-NHEJ pathway(5; 6; 7; 8):
1) Upon DSB generation, the ATM kinase recruits and phosphorilate H2AX at Serine 139 (ɣH2AX). Then, one Ku protein heterodimer (Ku70/Ku80) binds tightly at each DSB DNA termini.
2) The Ku complex is ring-shaped and serves as docking site for DNA PKcs.
3) The DNA PKcs from both DSB ends gets connected by bridge-like domains. This triggers an auto phosphorilation of DNA PKcs which catalyze the connection of both DNA termini. This also prevents the DNA from a premature or erroneous DNA degradation.
4) At this point, the Artemis nuclease is recruited by DNA PKcs (if needed for DSB resection). Artemis can be phosphorilated either by DNA PKcs or by ATM.
5) Finally the scaffolding protein XRCC4 allows the Ligase IV to binds to DNA and ligate both DSB ends fixing the DNA damage. The Ligase IV function it is enhanced by XLF/Cernunos factor.
References
1. Lindahl, T. And Barnes D. Repair of endogenous DNA damage. Cold Spring Harb. Symp. Quant. Biol. 2000 ;65127-133.
2. Branzei D, Foiani M. Regulation of DNA repair throughout the cell cycle. [Internet]. Nature reviews. Molecular cell biology. 2008 ;9(4):297-308.Available from: http://www.ncbi.nlm.nih.gov/pubmed/18...
3. Bennardo N, Cheng A, Huang N, Stark JM. Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair. PLoS Genetics. 2008 ;4(6):
4. Kim J, Minter-dykhouse K, Chen J. Signaling Networks Controlled by the MRN Complex and MDC1 During Early DNA Damage Responses. Molecular Carcinogenesis. 2006 ;408(May):403-408.
5. Lamarche BJ, Orazio NI, Weitzman MD. The MRN complex in double-strand break repair and telomere maintenance [Internet]. FEBS Letters. 2010 ;584(17):3682-3695.Available from: http://dx.doi.org/10.1016/j.febslet.2...
6. Shrivastav M, De Haro LP, Nickoloff Ja. Regulation of DNA double-strand break repair pathway choice. [Internet]. Cell research. 2008 ;18(1):134-47.Available from: http://www.ncbi.nlm.nih.gov/pubmed/18...
7. Weterings E, Chen DJ. The endless tale of non-homologous end-joining. [Internet]. Cell research. 2008 ;18(1):114-24.Available from: http://www.ncbi.nlm.nih.gov/pubmed/18...
8. Derheimer FA, Kastan MB. Multiple roles of ATM in monitoring and maintaining DNA integrity [Internet]. FEBS Letters. 2010 ;584(17):3675-3681.Available from: http://dx.doi.org/10.1016/j.febslet.2...