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DNA double-strand breaks: their cellular and clinical impact?

Oncogene volume 26, pages 7717–7719 (2007)Cite this article

DNA, the central store of our genetic information, constantly incurs damage from agents generated within the cell as well as chemicals or radiation that arise externally. Of the many different classes of damage, a DNA double-strand break (DSB) is arguably the most significant since, if unrepaired it can result in cell death and if misrepaired, it can cause chromosomal translocations, an early step in the aetiology of carcinogenesis. Endogenously generated reactive oxygen species primarily induce base damage and single strand breaks and it is unlikely that DNA DSBs are directly induced to any significant extent. However, DSBs may arise indirectly from two closely located single-strand breaks or during the repair of other lesions. They also arise when replication forks collapse, which may occur following the attempted replication of single-strand breaks or base damage. Indeed, a DSB is very likely the ultimate lesion induced by a wide range of DNA-damaging agents. The enhanced levels of endogenous chromosome breakage or chromosome rearrangements that have been observed in cells that fail to repair DSBs efficiently attests to the fact that they represent a relatively frequently encountered endogenous lesion (Karanjawala et al., 1999). Despite the constant onslaught of endogenous oxidative damage as well as frequently encountered exogenous DNA damage, genomic changes are a rare event and cells can undergo multiple rounds of replication without witnessing chromosomal alterations. This attests to the remarkable efficiency and evolutionary importance of the pathways that function in response to DSB induction.

While somatic cells invest enormous resources into maintaining genomic stability, the development of the immune response is a contrasting process that necessitates the generation of a high level of genetic diversity. Curiously, the immune system exploits the same machinery that serves to prevent genomic instability in somatic cells to create diversity during the development of the immune response (Bassing and Alt, 2004). Two important processes in this context are V(D)J recombination and class switch recombination, both of which involve programmed introduction of a DSB that interestingly arise by highly distinct and defined mechanisms. NHEJ-dependent rejoining then occurs in a manner that creates new end junctions (Taccioli et al., 1993). These processes represent exquisite examples of adaptive evolution that is regulated in a highly tissue specific manner. The process of meiotic recombination represents another example where the purpose is to create a level of genetic reassortment, which again exploits the cellular machinery that aids the maintenance of genomic stability in somatic cells. Yet again, the cell introduces a DSB as a first step in the process.

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Authors and Affiliations

  1. Genome Damage and Stability Centre, University of Sussex, East Sussex, UK

    P A Jeggo

  2. Radiation Biology and DNA Repair, Darmstadt University of Technology, Darmstadt, Germany

    M Löbrich

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  1. P A Jeggo
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  2. M Löbrich
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Correspondence to P A Jeggo or M Löbrich.

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Jeggo, P., Löbrich, M. DNA double-strand breaks: their cellular and clinical impact?. Oncogene 26, 7717–7719 (2007). https://doi.org/10.1038/sj.onc.1210868

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