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

1119 Citations (Scopus)

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

Fingerprint

DNA Replication
Oncogenes
DNA Damage
Cell Aging
DNA
Replicon
Replication Origin
Carcinogenesis
Cell Proliferation

ASJC Scopus subject areas

  • General

Cite this

Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., ... 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

Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. / Di Micco, Raffaella; Fumagalli, Marzia; Cicalese, Angelo; Piccinin, Sara; Gasparini, Patrizia; Luise, Chiara; Schurra, Catherine; Garré, Massimiliano; Giovanni Nuciforo, Paolo; Bensimon, Aaron; Maestro, Roberta; Giuseppe Pelicci, Pier; D'Adda Di Fagagna, Fabrizio.

In: Nature, Vol. 444, No. 7119, 2006, p. 638-642.

Research output: Contribution to journalArticle

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, vol. 444, no. 7119, pp. 638-642. https://doi.org/10.1038/nature05327
Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444(7119):638-642. https://doi.org/10.1038/nature05327
Di Micco, Raffaella ; Fumagalli, Marzia ; Cicalese, Angelo ; Piccinin, Sara ; Gasparini, Patrizia ; Luise, Chiara ; Schurra, Catherine ; Garré, Massimiliano ; Giovanni Nuciforo, Paolo ; Bensimon, Aaron ; Maestro, Roberta ; Giuseppe Pelicci, Pier ; D'Adda Di Fagagna, Fabrizio. / Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. In: Nature. 2006 ; Vol. 444, No. 7119. pp. 638-642.
@article{91d62bf6930b42c19c04c628358b84ec,
title = "Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication",
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.",
author = "{Di Micco}, Raffaella and Marzia Fumagalli and Angelo Cicalese and Sara Piccinin and Patrizia Gasparini and Chiara Luise and Catherine Schurra and Massimiliano Garr{\'e} and {Giovanni Nuciforo}, Paolo and Aaron Bensimon and Roberta Maestro and {Giuseppe Pelicci}, Pier and {D'Adda Di Fagagna}, Fabrizio",
year = "2006",
doi = "10.1038/nature05327",
language = "English",
volume = "444",
pages = "638--642",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7119",

}

TY - JOUR

T1 - Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication

AU - Di Micco, Raffaella

AU - Fumagalli, Marzia

AU - Cicalese, Angelo

AU - Piccinin, Sara

AU - Gasparini, Patrizia

AU - Luise, Chiara

AU - Schurra, Catherine

AU - Garré, Massimiliano

AU - Giovanni Nuciforo, Paolo

AU - Bensimon, Aaron

AU - Maestro, Roberta

AU - Giuseppe Pelicci, Pier

AU - D'Adda Di Fagagna, Fabrizio

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33845269825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845269825&partnerID=8YFLogxK

U2 - 10.1038/nature05327

DO - 10.1038/nature05327

M3 - Article

C2 - 17136094

AN - SCOPUS:33845269825

VL - 444

SP - 638

EP - 642

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7119

ER -