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

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

doi:10.1038/nature05327

Cited by 1,608 publications

(1,700 citation statements)

References 30 publications

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“…Although replication stress, defined as the deleterious effects of partially replicated DNA persisting in the nucleus, has been proposed as a mechanism for the observed DNA damage (Bartkova et al, 2006;Di Micco et al, 2006), our results would suggest that a significant part of the DNA damage and genetic instability observed in RAS-transformed cells originates from the oxidation products in the deoxynucleotide pool created by oncogenic RAS-induced ROS. It remains possible that oncogenic RAS-induced hyperproliferation (Di Micco et al, 2006) coupled with increased levels of oxidized guanine deoxynucleotides, leads to an even greater incorporation of these products into nuclear DNA during replication, in which they can contribute to replication stress.…”

Section: Resultsmentioning

confidence: 62%

“…Mouse models of OIS implicate DNA damage as a likely agent for triggering a proliferation arrest in vivo (Bartkova et al, 2006;Di Micco et al, 2006). Our study indicates that Figure 3 MTH1 expression does not show clear-cut effects on downstream oncogenic RAS signaling through the ERK pathway.…”

Section: Resultsmentioning

confidence: 70%

“…As RAS-induced senescence is accompanied by increased DSBs (Di Micco et al, 2006;Mallette et al, 2007), we assessed the effects of MTH1 overexpression on RAS-induced DNA damage. In the cell populations expressing H-RAS alone, a majority of cells (B85%) stained positive for three or more DSB foci, as detected by costaining cells with 53BP1 and gH2AX antibodies (Figures 2c and d).…”

Section: Resultsmentioning

confidence: 99%

“…Oncogene-induced senescence (OIS) (Di Micco et al, 2006), which occurs in response to increases in oncogenic RAS levels during tumor progression (Quintanilla et al, 1986;Algarra et al, 1998;Sarkisian et al, 2007) is believed to function as a major tumor-suppressor barrier. The senescence response to the RAS oncoprotein has been ascribed to its production of reactive oxygen species (ROS) (Irani et al, 1997;Lee et al, 1999) and to the resulting induction of a DNA damage response (DDR) (Di Micco et al, 2006;Mallette et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The senescence response to the RAS oncoprotein has been ascribed to its production of reactive oxygen species (ROS) (Irani et al, 1997;Lee et al, 1999) and to the resulting induction of a DNA damage response (DDR) (Di Micco et al, 2006;Mallette et al, 2007). However, the connection between these two RAS-induced effects has been unclear.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

et al. 2010

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Approximately 20% of tumors contain activating mutations in the RAS family of oncogenes. As tumors progress to higher grades of malignancy, the expression of oncogenic RAS has been reported to increase, leading to an oncogene-induced senescence (OIS) response. Evasion of this senescence barrier is a hallmark of advanced tumors indicating that OIS serves a critical tumorsuppressive function. Induction of OIS has been attributed to either RAS-mediated production of reactive oxygen species (ROS) or to induction of a DNA damage response (DDR). However, functional links between these two processes in triggering the senescent phenotype have not been explicitly described. Our previous work has shown that, in cultured untransformed cells, preventing elimination of oxidized guanine deoxyribonucleotides, which was achieved by suppressing expression of the cellular 8-oxodGTPase, human MutT homolog 1 (MTH1), sufficed to induce a DDR as well as premature senescence. Here, we demonstrate that overexpression of MTH1 can prevent the oncogenic H-RAS-induced DDR and attendant premature senescence, although it does not affect the observed elevation in ROS levels produced by RAS oncoprotein expression. Conversely, we find that loss of MTH1 preferentially induces an in vitro proliferation defect in tumorigenic cells overexpressing oncogenic RAS. These results indicate that the guanine nucleotide pool is a critical target for intracellular ROS produced by oncogenic RAS and that RAS-transformed cells require robust MTH1 expression to proliferate.

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Section: Resultsmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

et al. 2010

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Regulation of cellular senescence via the FOXO4‐p53 axis

Bourgeois

Madl

2018

FEBS Letters

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Forkhead box O (FOXO) and p53 proteins are transcription factors that regulate diverse signalling pathways to control cell cycle, apoptosis and metabolism. In the last decade both FOXO and p53 have been identified as key players in aging, and their misregulation is linked to numerous diseases including cancers. However, many of the underlying molecular mechanisms remain mysterious, including regulation of ageing by FOXOs and p53. Several activities appear to be shared between FOXOs and p53, including their central role in the regulation of cellular senescence. In this review, we will focus on the recent advances on the link between FOXOs and p53, with a particular focus on the FOXO4‐p53 axis and the role of FOXO4/p53 in cellular senescence. Moreover, we discuss potential strategies for targeting the FOXO4‐p53 interaction to modulate cellular senescence as a drug target in treatment of aging‐related diseases and morbidity.

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Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

et al. 2017

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Medulloblastomas are the most common, and often fatal, paediatric brain tumours that feature high genomic instability, frequent infection by human cytomegalovirus (HCMV) and resistance to radiation and chemotherapy. The causes of the pronounced chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies remain largely unknown. To address these issues, here we have combined immunohistochemical analysis of a series of 25 paediatric medulloblastomas, complemented by medulloblastoma cell culture models including experimental HCMV infection. Using eight established immunohistochemical markers to assess the status of the DDR machinery, we found pronounced endogenous DNA damage signalling (cH2AX marker) and robust constitutive activation of both the ATM-Chk2 and ATR-Chk1 DNA damage checkpoint kinase cascades, yet unexpectedly modest p53 tumour suppressor activation, across our medulloblastoma cohort. Most tumours showed high proliferation (Ki67 marker), variable oxidative DNA damage (8-oxoguanine lesions) and formation of 53BP1 nuclear 'bodies', the latter indicating (along with ATR-Chk1 signalling) endogenous replication stress. The bulk of the clinical specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing responses of normal cells and medulloblastoma cells to HCMV infection, including differential subcellular mislocalization and enhancement of replication stress-related 53BP1 body formation, the latter in cell-non-autonomous manner. Overall, our results strongly indicate that Abbreviations 53BP1, p53-binding protein 1; ATCC, American Type Culture Collection; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia mutated and Rad3 related; Chk1, checkpoint kinase 1; Chk2, checkpoint kinase 2; COX-2, cyclooxygenase-2; DDR, DNA damage response; FBS, fetal bovine serum; FISH, fluorescence in situ hybridization; GFAP, glial fibrillary acidic protein; HCMV, human cytomegalovirus; IDH, isocitrate dehydrogenase; IE72, immediate early 72; Ini-1, integrase interactor 1; MAP-2, microtubule-associated protein 2; MDC1, mediator of DNA damage checkpoint protein 1; MOI, multiplicity of infection; NGS, next-generation sequencing; Olig2, oligodendrocyte transcription factor 2; PBS, phosphate-buffered saline; PGE2, prostaglandin E2; SHH, sonic hedgehog; WNT, wingless; γH2AX, phosphorylated histone H2AX. in human medulloblastomas, the DDR checkpoint barrier is widely activated, at least in part due to replication stress. Furthermore, we propose that unorthodox p53 defects other than mutations may allow high proliferation despite the ongoing checkpoint signalling and that the highly prevalent HCMV may impact the medulloblastoma host cell replication stress and DNA repair. Collectively, the scenario we report here likely fuels genomic instability ...

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

Cited by 1,608 publications

References 30 publications

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

Enhanced elimination of oxidized guanine nucleotides inhibits oncogenic RAS-induced DNA damage and premature senescence

Regulation of cellular senescence via the FOXO4‐p53 axis

Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

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