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


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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    • "Among other radiobiological factors, intrinsic radiation sensitivity of tumour cells represents a major component attributing to treatment outcome [3,12–14]. Intrinsic cellular radiation sensitivity correlates with the number of residual unrepaired DNA double strand breaks (DSBs) [15] [16] [17]. Therefore, assessment of intrinsic radiation sensitivity through quantification of DNA DSBs has become increasingly utilized in translation cancer research [18] [19] [20]. "
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    Radiotherapy and Oncology 08/2015; 116(3). DOI:10.1016/j.radonc.2015.08.006 · 4.36 Impact Factor
    • "This is followed by a slow exponential phase spanning many hours that tackles the remainder, not all of which are necessarily repaired correctly. Two major pathways are used to rejoin radiationinduced DSB, non-homologous end-joining (NHEJ) and homologous recombination repair [65]. NHEJ rejoins break ends in an error-prone manner, frequently causing microdeletions or -insertions at the breakpoint and, when multiple breaks coincide, joining break ends derived from different DSB [66]. "
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    ABSTRACT: The response of human normal tissues to radiotherapy fraction size is often described in terms of cellular recovery, but the causal links between cellular and tissue responses to ionising radiation are not necessarily straightforward. This article reviews the evidence for a cellular basis to clinical fractionation sensitivity in normal tissues and discusses the significance of a long-established inverse association between fractionation sensitivity and proliferative indices. Molecular mechanisms of fractionation sensitivity involving DNA damage repair and cell cycle control are proposed that will probably require modification before being applicable to human cancer. The article concludes by discussing the kind of correlative research needed to test for and validate predictive biomarkers of tumour fractionation sensitivity. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
    Clinical Oncology 06/2015; 27(10). DOI:10.1016/j.clon.2015.06.006 · 3.40 Impact Factor
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    • "Therefore, mechanisms may exist within nucleoli to suppress NHEJ in favor of HR. Possible players include DNA-PK and 53BP1 (Jackson 2002; Panier and Boulton 2014). DNA-PK and Ku are not detected at nucleolar caps and presumably are unable to suppress end resection. "
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    ABSTRACT: DNA double-strand breaks (DSBs) are repaired by two main pathways: nonhomologous end-joining and homologous recombination (HR). Repair pathway choice is thought to be determined by cell cycle timing and chromatin context. Nucleoli, prominent nuclear subdomains and sites of ribosome biogenesis, form around nucleolar organizer regions (NORs) that contain rDNA arrays located on human acrocentric chromosome p-arms. Actively transcribed rDNA repeats are positioned within the interior of the nucleolus, whereas sequences proximal and distal to NORs are packaged as heterochromatin located at the nucleolar periphery. NORs provide an opportunity to investigate the DSB response at highly transcribed, repetitive, and essential loci. Targeted introduction of DSBs into rDNA, but not abutting sequences, results in ATM-dependent inhibition of their transcription by RNA polymerase I. This is coupled with movement of rDNA from the nucleolar interior to anchoring points at the periphery. Reorganization renders rDNA accessible to repair factors normally excluded from nucleoli. Importantly, DSBs within rDNA recruit the HR machinery throughout the cell cycle. Additionally, unscheduled DNA synthesis, consistent with HR at damaged NORs, can be observed in G1 cells. These results suggest that HR can be templated in cis and suggest a role for chromosomal context in the maintenance of NOR genomic stability. © 2015 van Sluis and McStay; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 06/2015; 29(11). DOI:10.1101/gad.260703.115 · 10.80 Impact Factor
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