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DNA double-strand breaks: signaling, repair and the cancer connection

Nature Genetics volume 27, pages 247–254 (2001)Cite this article

Abstract

To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and post-transcriptional activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death. An inability to respond properly to, or to repair, DNA damage leads to genetic instability, which in turn may enhance the rate of cancer development. Indeed, it is becoming increasingly clear that deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most, if not all, human cancers. Here we describe recent progress in our understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation—the DNA double-strand break (DSB). Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.

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Figure 1: Pathways of DSB repair.

Bob Crimi

Figure 2: Components of DNA DSB repair pathways.

Bob Crimi

Figure 3: Repair genes as caretakers of the genome.

Bob Crimi

Figure 4: Signaling of DSBs.

Bob Crimi

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Acknowledgements

We thank members of the Khanna and Jackson Laboratories for discussions, and J. Bradbury for editorial and scientific advice. We apologize to colleagues whose work we could not cite due to space restrictions. The Khanna laboratory is funded by grants from the National Health and Medical Research Council (Australia), the Queensland Cancer Fund (Australia) and the Susan G. Komen Breast Cancer Foundation (USA). The Jackson Laboratory is funded by grants from the Cancer Research Campaign, the Association for International Cancer Research and the A-T Medical Research Trust.

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  1. The Queensland Institute of Medical Research, and Department of Pathology, University of Queensland, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia

    Kum Kum Khanna

  2. Wellcome Trust and Cancer Research Campaign Institute of Cancer and Developmental Biology, and Department of Zoology, University of Cambridge, Cambridge, UK

    Stephen P. Jackson

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Correspondence to Kum Kum Khanna.

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Khanna, K., Jackson, S. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27, 247–254 (2001). https://doi.org/10.1038/85798

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