DNA double-strand break repair
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DNA double strand breaks represent the most threatening lesion to the integrity of the genome in cells exposed to ionizing radiation and radiomimetic chemicals. Those breaks are recognized, signaled to cell cycle checkpoints and repaired by protein complexes. Double-strand breaks (DSBs), in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements.
Two mechanisms exist to repair DNA double strand breaks:
1. non-homologous end joining (NHEJ)
2. recombinational repair (also known as template-assisted repair or homologous recombination repair).
1. non-homologous end joining (NHEJ)
DNA ligase is an enzyme that joins broken nucleotides together by catalyzing the formation of an internucleotide ester bond between the phosphate backbone and the deoxyribose nucleotides.
DNA Ligase IV is a specialized DNA Ligase that forms a complex with the cofactor XRCC4. In NHEJ, DNA Ligase IV directly joins the two ends. To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.
NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms translocations.
NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination.
There are "backup" NHEJ pathways in higher eukaryotes.
Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.
Recombinational repair requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis.
This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template.
DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.
Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNA?s state of supercoiling, which is especially common in regions near an open replication fork.
Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.
Pathology
Anomalies in DNA double strand breaks repair can cause several human diseases as ATM and Ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia.
Anomalies in DNA double strand breaks repair can cause several human diseases:
- ATM and Ataxia telangiectasia
- Nijmegen breakage syndrome
- Fanconi anemia
See also
DNA double-strand breaks
DNA repair
DNA damage (DNA lesions)
References
O?Driscoll M, Jeggo PA. The role of double-strand break repair - insights from human genetics. Nat Rev Genet. 2006 Jan;7(1):45-54. PMID: 6369571
Karagiannis TC, El-Osta A. Double-strand breaks: signaling pathways and repair mechanisms. Cell Mol Life Sci. 2004 Sep;61(17):2137-47. PMID: 15338043
Kobayashi J, Antoccia A, Tauchi H, Matsuura S, Komatsu K. NBS1 and its functional role in the DNA damage response. DNA Repair (Amst). 2004 Aug-Sep;3(8-9):855-61. PMID: 15279770
Matsuura S, Kobayashi J, Tauchi H, Komatsu K. Nijmegen breakage syndrome and DNA double strand break repair by NBS1 complex. Adv Biophys. 2004;38:65-80. PMID: 15493328
Valerie K, Povirk LF. Regulation and mechanisms of mammalian double-strand break repair. Oncogene. 2003 Sep 1;22(37):5792-812. PMID: 12947387
Petrini JH, Stracker TH. The cellular response to DNA double-strand breaks : defining the sensors and mediators. Trends Cell Biol. 2003 Sep ;13(9):458-62. PMID : 12946624
Pierce AJ, Stark JM, Araujo FD, Moynahan ME, Berwick M, Jasin M. Double-strand breaks and tumorigenesis. Trends Cell Biol. 2001 Nov;11(11):S52-9. PMID: 11684443
Aguilera A. Double-strand break repair: are Rad51/RecA?DNA joints barriers to DNA replication? Trends Genet. 2001 Jun;17(6):318-21. PMID: 11377793
Haber JE. Partners and pathways repairing a double-strand break. Trends Genet. 2000 Jun;16(6):259-64. PMID: 10827453