Article

Jackson SP. Sensing and repairing DNA double-strand breaks

Wellcome Trust and Cancer Research UK Institute of Cancer and Developmental Biology, Tennis Court Road, Cambridge CB2 1QR, UK.
Carcinogenesis (Impact Factor: 5.33). 06/2002; 23(5):687-96. DOI: 10.1093/carcin/23.5.687
Source: PubMed

ABSTRACT

The DNA double-strand break (DSB) is the principle cytotoxic lesion for ionizing radiation and radio-mimetic chemicals but can also be caused by mechanical stress on chromosomes or when a replicative DNA polymerase encounters a DNA single-strand break or other type of DNA lesion. DSBs also occur as intermediates in various biological events, such as V(D)J recombination in developing lymphoid cells. Inaccurate repair or lack of repair of a DSB can lead to mutations or to larger-scale genomic instability through the generation of dicentric or acentric chromosomal fragments. Such genome changes may have tumourigenic potential. In other instances, DSBs can be sufficient to induce apoptosis. Because of the threats posed by DSBs, eukaryotic cells have evolved complex and highly conserved systems to rapidly and efficiently detect these lesions, signal their presence and bring about their repair. Here, I provide an overview of these systems, with particular emphasis on the two major pathways of DSB repair: non-homologous end-joining and homologous recombination. Inherited or acquired defects in these pathways may lead to cancer or to other human diseases, and may affect the sensitivity of patients or tumour cells to radiotherapy and certain chemotherapies. An increased knowledge of DSB repair and of other DNA DSB responses may therefore provide opportunities for developing more effective treatments for cancer.

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    • "XRCC2, XRCC3 are DSB repair genes participate in homologous recombination repair pathway to maintain chromosome stability and DNA damage repair (Liu et al 1998, Pierce et al 1999, Thacker and Zdzienicka, 2004). The XRCC4, XRCC5, XRCC6, XRCC7 are DSB repair genes, involved in homologous recombination repair (HRR) pathway and nonhomologous end joining (NHEJ) (Jackson, 2002, Helleday, 2003, Mari et al., 2006). The polymorphisms in DNA repair genes are associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of cancer. "
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    DESCRIPTION: To identify the risk factors other than tobacco and alcohol for the development of head and neck cancer, functional polymorphisms of DNA repair genes including XRCC1 Arg194Trp in the exon 6, Arg280His in the exon 9, Arg399Gln in the exon 10, XRCC2 Arg188His in the exon 3, XRCC3 Thr241Met in the exon 7, XRCC4 codon 247, XRCC4 G1394T, XRCC4 intron7, XRCC5 2R/1R/0R, XRCC6 61 (C>G) and XRCC7 6721 (G>T) were studied among rural population of Maharashtra. The XRCC genes were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to elucidate the specific changes in the gene region. The result from our study showed that XRCC1 A399G in exon 10 (OR= 3.69; 95%CI= (2.34-5.51); p= <0.0001) XRCC4-2 (G1394T) OR=6.53; 95%CI=(4.71-9.05); p= <0.0001), XRCC5 (0R/0R) OR=1.97; 95%CI=(1.15-3.26); p= <0.0001) and XRCC7 (6721 T/T) OR=11.58; 95%CI=(7.44-18.02); p= <0.0001) genotypes significantly increased the risk of head and neck cancer. This study indicates that variant types of XRCC1, XRCC4, XRCCC5 and XRCC7 genes play a role in modifying genetic susceptibility of individual to head and neck cancer. Thus, the consistent findings from this case-control study suggest that selected DNA repair genes represent genetic determinants in oral carcinogenesis along with other risk factors in the rural Indian population.
    Full-text · Research · Feb 2016
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    • "XRCC2, XRCC3 are DSB repair genes participate in homologous recombination repair pathway to maintain chromosome stability and DNA damage repair (Liu et al 1998, Pierce et al 1999, Thacker and Zdzienicka, 2004). The XRCC4, XRCC5, XRCC6, XRCC7 are DSB repair genes, involved in homologous recombination repair (HRR) pathway and nonhomologous end joining (NHEJ) (Jackson, 2002, Helleday, 2003, Mari et al., 2006). The polymorphisms in DNA repair genes are associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of cancer. "
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    DESCRIPTION: Role of genetic polymorphisms in DNA repair genes (XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, XRCC6, XRCC7) in head and neck cancer susceptibility in rural Indian population A hospital based case-control study from south- western Maharashtra
    Full-text · Research · Feb 2016
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    • "HR restores the original DNA sequence using DNA from an intact sister chromatid as a template. Although error prone, NHEJ also helps maintain genome function (Corneo et al., 2007;Hefferin and Tomkinson, 2005;Jackson, 2002;Lieber, 2010;Moore and Haber, 1996;Wyman and Kanaar, 2006;Yan et al., 2007). Classical NHEJ (C- NHEJ) repairs DSBs in all phases of the cell cycle except the M phase, while HR activity is restricted to late S and G2 phases (Ciccia and Elledge, 2010;Lieber et al., 2003;Orthwein et al., 2014). "
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    ABSTRACT: Mitochondrial DNA (mtDNA) deletions are associated with various mitochondrial disorders. The deletions identified in humans are flanked by short directly-repeated mitochondrial DNA sequences; however, the mechanism of such DNA rearrangements is yet to be elucidated. In contrast to nuclear DNA (nDNA), mtDNA is more exposed to oxidative damage that may result in double-strand breaks (DSBs). Although, DSB repair in nDNA is well studied, repair mechanisms in mitochondria are not characterized. In the present study, we investigate the mechanisms of DSB repair in mitochondria using in vitro and ex vivo assays. While classical-NHEJ (C-NHEJ) is undetectable, microhomology mediated alternative-NHEJ efficiently repairs DSBs in mitochondria. Interestingly, robust MMEJ (Microhomology Mediated End Joining) was observed with DNA substrates bearing 5, 8, 10, 13, 16, 19 and 22 nt microhomology. Furthermore, MMEJ efficiency was enhanced with an increase in the length of homology. Western blotting, immunoprecipitation and protein inhibition assays suggest the involvement of CtIP, FEN1, MRE11 and PARP1 in mitochondrial MMEJ. Knockdown studies, in conjunction with other experiments demonstrated that DNA LIGASE III, but not LIGASE IV or LIGASE I, is primarily responsible for the final sealing of DSBs during mitochondrial MMEJ. These observations highlight the central role of MMEJ in maintenance of the mammalian mitochondrial genome integrity and is likely relevant for deletions observed in many human mitochondrial disorders.
    Full-text · Article · Nov 2015 · Molecular biology of the cell
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