1. IFOM Foundation – FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy
2. Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
3. Experimental Oncology 1, Centro di Riferimento Oncologico CRO IRCCS, 33081 Aviano, Italy
4. Genome Stability Unit, 75724 Pasteur Institute, Paris, France
5. Genomic Vision, 75724 Paris, France

Correspondence to: Fabrizio d'Adda di Fagagna¹ Correspondence and requests for materials should be addressed to F.d.A.d.F. (Email: fabrizio.dadda@ifom-ieo-campus.it).

Early tumorigenesis is associated with the engagement of the DNA-damage checkpoint response (DDR)^{1, 2}. Cell proliferation and transformation induced by oncogene activation are restrained by cellular senescence^{3, 4, 5, 6}. It is unclear whether DDR activation and oncogene-induced senescence (OIS) are causally linked. Here we show that senescence, triggered by the expression of an activated oncogene (H-RasV12) in normal human cells, is a consequence of the activation of a robust DDR. Experimental inactivation of DDR abrogates OIS and promotes cell transformation. DDR and OIS are established after a hyper-replicative phase occurring immediately after oncogene expression. Senescent cells arrest with partly replicated DNA and with DNA replication origins having fired multiple times. In vivo DNA labelling and molecular DNA combing reveal that oncogene activation leads to augmented numbers of active replicons and to alterations in DNA replication fork progression. We also show that oncogene expression does not trigger a DDR in the absence of DNA replication. Last, we show that oncogene activation is associated with DDR activation in a mouse model in vivo. We propose that OIS results from the enforcement of a DDR triggered by oncogene-induced DNA hyper-replication.

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