The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence

Mallette, Frédérick A.; Gaumont-Leclerc, Marie-France; Ferbeyre, Gerardo

doi:10.1101/gad.1487307

Cited by 362 publications

(354 citation statements)

References 41 publications

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“…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%

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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: 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%

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

et al. 2010

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“…Given that such DDR activation was not provoked by therapy and analogous checkpoint induction was recapitulated in multiple xenograft and cell culture models of oncogene activation (Bartkova et al, 2005a(Bartkova et al, , 2006Gorgoulis et al, 2005;Di Micco et al, 2006;Mallette et al, 2007), these studies suggest that the DDR network may function as a biological barrier against cancer progression. Conceptually, this evidence furthermore implies that the activated DDR barrier creates growth-suppressive conditions under which inactivating aberrations within the DDR machinery are selected for, and thereby allowing such early lesions to overcome the DDR-induced senescence and/or cell-death pathways and to progress towards full malignancy.…”

Section: Introductionmentioning

confidence: 91%

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

et al. 2007

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The ataxia-telangiectasia-mutated (ATM) kinase is a key transducer of DNA damage signals within the genome maintenance machinery and a tumour suppressor whose germline mutations predispose to familial breast cancer. ATM signalling is constitutively activated in early stages of diverse types of human malignancies and cell culture models in response to oncogene-induced DNA damage providing a barrier against tumour progression. As BRCA1 and BRCA2 are also components of the genome maintenance network and their mutations predispose to breast cancer, we have examined the ATM expression in human breast carcinomas of BRCA1/2 mutation carriers, sporadic cases and familial non-BRCA1/2 patients. Our results show that ATM protein expression is aberrantly reduced more frequently among BRCA1 (33%; P ¼ 0.0003) and BRCA2 (30%; P ¼ 0.0009) tumours than in non-BRCA1/2 tumours (10.7%). Furthermore, the non-BRCA1/2 tumours with reduced ATM expression were more often estrogen receptor (ER) negative (P ¼ 0.0002), progesterone receptor (PR) negative (P ¼ 0.004) and were of higher grade (P ¼ 0.0004). In our series of 1013 non-BRCA1/2 cases, ATM was more commonly deficient (20%; P ¼ 0.0006) and p53 was overabundant (47%; Po0.0000000001) among the difficult-to-treat ER/PR/ ERBB2-triple-negative subset of tumours compared with cases that expressed at least one of these receptors (10 and 16% of aberrant ATM and p53, respectively). We propose a model of 'conditional haploinsufficiency' for BRCA1/2 under conditions of enhanced DNA damage in precancerous lesions resulting in more robust activation and hence increased selection for inactivation or loss of ATM in tumours of BRCA1/2 mutation carriers, with implications for genomic instability and curability of diverse subsets of human breast cancer.

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“…The DNA damage accumulated during such deregulated DNA synthesis also activates p53 via the ATM and ATR damage signaling pathways, leading to p21 induction and permanent cell cycle arrest. 37,38 In addition to directly preventing DNA replication by inhibiting Cdk2, p21 also blocks the inactivating phosphorylation of pRb by Cdk2 and Cdk4/6 ( Fig. 1), which is a key mechanism in the senescence program.…”

Section: Senescence As An Irreversible G1 Arrestmentioning

confidence: 99%

Senescence from G2 arrest, revisited

2015

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The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence

Cited by 362 publications

References 41 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

The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer

Senescence from G2 arrest, revisited

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