Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication

Raffaella Di Micco, Marzia Fumagalli, Angelo Cicalese, Sara Piccinin, Patrizia Gasparini, Chiara Luise, Catherine Schurra, Massimiliano Garré, Paolo Giovanni Nuciforo, Aaron Bensimon, Roberta Maestro, Pier Giuseppe Pelicci, Fabrizio D'Adda Di Fagagna

Research output: Contribution to journalArticle

Abstract

Early tumorigenesis is associated with the engagement of the DNA-damage checkpoint response (DDR). Cell proliferation and transformation induced by oncogene activation are restrained by cellular senescence. 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.

Original languageEnglish
Pages (from-to)638-642
Number of pages5
JournalNature
Volume444
Issue number7119
DOIs
Publication statusPublished - 2006

ASJC Scopus subject areas

  • General

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    Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., Schurra, C., Garré, M., Giovanni Nuciforo, P., Bensimon, A., Maestro, R., Giuseppe Pelicci, P., & D'Adda Di Fagagna, F. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 444(7119), 638-642. https://doi.org/10.1038/nature05327