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Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints


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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Figure 1: Oncogene-induced senescence is dependent on the DNA DSB checkpoint.
Figure 2: DNA replication stress in cells undergoing oncogene-induced senescence.
Figure 3: Cosegregation of senescence and DNA damage response markers, but not p16 INK4A, in human precancerous and cancerous lesions.
Figure 4: Oncogene-induced senescence acts as a barrier to invasiveness and tumorigenesis.

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

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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).

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