Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication.
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.
Di Micco
Raffaella
R
IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy.
Fumagalli
Marzia
M
Cicalese
Angelo
A
Piccinin
Sara
S
Gasparini
Patrizia
P
Luise
Chiara
C
Schurra
Catherine
C
Garre'
Massimiliano
M
Nuciforo
Paolo Giovanni
PG
Bensimon
Aaron
A
Maestro
Roberta
R
Pelicci
Pier Giuseppe
PG
d'Adda di Fagagna
Fabrizio
F
D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D004261:DNA Replication; D011905:Genes, ras; D005819:Genetic Markers; D006801:Humans; D051379:Mice
D005819:Genetic Markers