Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints (original) (raw)

Nature volume 444, pages 633–637 (2006) Cite this article

Abstract

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest1,2, whereas a second barrier is mediated by oncogene-induced senescence3,4,5,6. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.

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Acknowledgements

We thank Z. Lygerou and S. Taraviras for advice and reagents and M. Sideridou, N. Youroukos and M.-H. Lee for technical assistance. This work was supported by the Danish Cancer Society, the Danish National Research Foundation and the European Commission ‘Active p53’ and ‘Mutant p53’ Integrated Projects (J.B.); the National Cancer Institute, USA and the Swiss National Foundation (T.D.H.); the UICC (T.D.H. and V.G.G.); the Greek General Secretariat of Technology PENED program (V.G.G.); and the Swedish Cancer Society and Swedish Pain Relief Foundation (T.H.).

Author information

Author notes

  1. Jirina Bartkova, Nousin Rezaei and Michalis Liontos: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100, Copenhagen, Denmark
    Jirina Bartkova, Frederic Tort, Kasper Fugger, Jiri Lukas & Jiri Bartek
  2. The Wistar Institute, Pennsylvania, 19104-4268, Philadelphia, USA
    Nousin Rezaei & Thanos D. Halazonetis
  3. Department of Histology and Embryology, School of Medicine, University of Athens, GR-11527, Athens, Greece
    Michalis Liontos, Panagiotis Karakaidos, Leandros-Vassilios F. Vassiliou, Katerina Niforou, Christos Kittas & Vassilis G. Gorgoulis
  4. Institute of Biology, Demokritos National Center for Scientific Research, GR-15310, Athens, Greece
    Dimitris Kletsas
  5. Department of Genetics, Microbiology and Toxicology, Stockholm University, S-10691, Stockholm, Sweden
    Natalia Issaeva, Fredrik Johansson & Thomas Helleday
  6. Department of Physiology, School of Medicine, University of Ioannina, GR-45110, Ioannina, Greece
    Evangelos Kolettas
  7. Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, GR-11635, Athens, Greece
    Vassilis C. Zoumpourlis
  8. Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-2144, USA
    Munenori Takaoka & Hiroshi Nakagawa
  9. Department of Pathology, University Hospital, DK-2100, Copenhagen, Denmark
    Maxwell Sehested
  10. Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, Aarhus N, DK-8200, Denmark
    Claus L. Andersen, Lars Dyrskjot & Torben Ørntoft
  11. The Institute for Cancer Studies, University of Sheffield, Sheffield, S10 2RX, UK
    Thomas Helleday
  12. Department of Molecular Biology, University of Geneva, CH-1211, Geneva, 4, Switzerland
    Thanos D. Halazonetis

Authors

  1. Jirina Bartkova
  2. Nousin Rezaei
  3. Michalis Liontos
  4. Panagiotis Karakaidos
  5. Dimitris Kletsas
  6. Natalia Issaeva
  7. Leandros-Vassilios F. Vassiliou
  8. Evangelos Kolettas
  9. Katerina Niforou
  10. Vassilis C. Zoumpourlis
  11. Munenori Takaoka
  12. Hiroshi Nakagawa
  13. Frederic Tort
  14. Kasper Fugger
  15. Fredrik Johansson
  16. Maxwell Sehested
  17. Claus L. Andersen
  18. Lars Dyrskjot
  19. Torben Ørntoft
  20. Jiri Lukas
  21. Christos Kittas
  22. Thomas Helleday
  23. Thanos D. Halazonetis
  24. Jiri Bartek
  25. Vassilis G. Gorgoulis

Corresponding authors

Correspondence toJirina Bartkova, Thanos D. Halazonetis or Jiri Bartek.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Bartkova, J., Rezaei, N., Liontos, M. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.Nature 444, 633–637 (2006). https://doi.org/10.1038/nature05268

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Editorial Summary

Cancer and cell senescence

Cancer is commonly thought of as uncontrolled cellular proliferation, but in the early stages of many cancers, oncogene expression is associated with cellular senescence. A possible explanation for this has now been found. Two groups report a link between oncogene-induced senescence and the DNA damage response. Activated oncogenes can cause aberrant DNA replication and thereby DNA damage that can lead to cell senescence. Cellular senescence was found previously to be a barrier to tumorigenesis in vivo, so oncogene-induced senescence may be an innate defence against cancer. But its effectiveness is often disabled by further mutations. Understanding the relationship between cell senescence and tumour formation may aid in the development of diagnostic and prognostic tools based on senescence markers.

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