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DNA damage signalling guards against activated oncogenes and tumour progression

Oncogene volume 26, pages 7773–7779 (2007)Cite this article

Abstract

DNA damage response (DDR), the guardian of genomic integrity, emerges as an oncogene-inducible biological barrier against progression of cancer beyond its early stages. Recent evidence from both cell culture and animal models as well as analyses of clinical specimens show that activation of numerous oncogenes and loss of some tumour suppressors result in DNA replication stress and DNA damage that alarm the cellular DDR machinery, a multifaceted response orchestrated by the ATR–Chk1 and ATM–Chk2 kinase signalling pathways. Such activation of the DDR network leads to cellular senescence or death of oncogene-transformed cells, resulting in delay or prevention of tumorigenesis. At the same time, the ongoing chronic DDR activation creates selective pressure that eventually favours outgrowth of malignant clones with genetic or epigenetic defects in the genome maintenance machinery, such as aberrations in the ATM–Chk2–p53 cascade and other DDR components. Furthermore, the executive DDR machinery is shared by at least two anticancer barriers, as both the oncogene-induced DNA replication stress and telomere shortening impact the cell fate decisions through convergence on DNA damage signalling. In this study, we highlight recent advances in this rapidly evolving area of cancer research, with particular emphasis on mechanistic insights, emerging issues of special conceptual significance and discussion of major remaining challenges and implications of the concept of DDR as a tumorigenesis barrier for experimental and clinical oncology.

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Acknowledgements

Research in authors’ laboratories is supported by the Danish Cancer Society, the Danish National Research Foundation, the European Commission (integrated projects ‘Active p53’, ‘DNA repair’ and ‘Mutant p53’), MSM (No. 6198959216), the Novo Nordisk Foundation and the Danish National Research Council.

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Authors and Affiliations

  1. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark

    J Bartek, J Bartkova & J Lukas

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  1. J Bartek
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  2. J Bartkova
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  3. J Lukas
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Correspondence to J Bartek.

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Bartek, J., Bartkova, J. & Lukas, J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26, 7773–7779 (2007). https://doi.org/10.1038/sj.onc.1210881

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