Key Points
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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.
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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.
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Physiological DSBs result during V(D)J recombination and class-switch recombination. The rejoining phase of these two processes uses NHEJ.
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NHEJ is typically imprecise in multicellular eukaryotes, making it the only main DNA-repair pathway that is error prone.
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Because of its error-prone nature, NHEJ might contribute to cancer and ageing.
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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-PKcs), is responsible for trimming the DNA ends in NHEJ.
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.
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DATABASES
LocusLink
Swiss-Prot
Glossary
- ROBERTSONIAN TRANSLOCATION
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A type of chromosomal translocation in which two acrocentric chromosomes become linked at their centromeres.
- HAPLOINSUFFICIENCY
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In a diploid organism, if both alleles are wild type or mutant, then the phenotype can be described as wild type or mutant. If one allele is mutant and the other is wild type, the organism typically appears wild type. However, for some genes, a phenotype arises even in these heterozygotes because half of the amount of the encoded protein is not sufficient. This is known as haploinsufficiency.
- RAG COMPLEX
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Immunoglobin heavy and light genes and T-cell-receptor genes are assembled from germline variable- and constant-region gene segments by a DNA recombination process in B and T cells, respectively. These gene rearrangements depend on the expression of recombination-activating genes (RAG)1 and RAG2.
- V(D)J RECOMBINATION
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A specialized form of recombination that assembles the genes that encode lymphocyte antigen receptors from variable (V), diversity (D) and joining (J) gene segments. Double-stranded DNA breaks are introduced between the V, D and J segments and DNA-repair proteins then join the segments together.
- TYPE II TOPOISOMERASE
-
Whereas type I topoisomerases nick one strand and thereby change supercoiling (actually the linking number) in steps of one, type II topoisomerases make a double-stranded DNA break, thereby changing the supercoiling in steps of two.
- BREATHING
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The hydrogen bonds within the Watson–Crick DNA helix are thought to transiently and focally 'melt'. Such breathing varies with the local sequence, particularly the A–T content. The length of DNA, duration and frequency of such sites of breathing has been studied for short test sequences, but is much less certain for longer stretches of DNA.
- RAD50–MRE11–NBS1 COMPLEX
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This complex is involved in homologous recombination, along with other proteins such as RAD51, RAD52, RAD54, RAD55, RAD57, XRCC2, XRCC3 and possibly BRCA1 and BRCA2. Patients who are mutant for NBS1 (known as XRS2 in yeast) have Nijmegen breakage syndrome, which includes microcephaly, increased malignancy and chromosomal instability. Mice with hypomorphic alleles of Rad50 have normal V(D)J recombination49,50,51, which indicates that this complex does not have a primary role in this pathway.
- CLASS-SWITCH RECOMBINATION
-
This is the process by which the immunoglobulin heavy-chain isotype changes from IgM to IgG1, IgG2, IgG3, IgG4, IgA1, IgA2 or IgE in humans (and similar isotypes in mice and other vertebrates). It involves a double-stranded DNA break (DSB) at the switch regions (which are repetitive, G-rich and several kilobases in length) at the immunoglobulin heavy-chain locus. The DSBs are rejoined by some of the components of the non-homologous end-joining pathway.
- TOROIDAL
-
Doughnut-shaped.
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Lieber, M., Ma, Y., Pannicke, U. et al. Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4, 712–720 (2003). https://doi.org/10.1038/nrm1202
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DOI: https://doi.org/10.1038/nrm1202
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