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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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.).

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Author notes

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


  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


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Reprints and permissions information is available at The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jirina Bartkova or Thanos D. Halazonetis or Jiri Bartek.

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