Transgenic expression of E2F3a causes DNA damage leading to ATM-dependent apoptosis

Abstract

Many early stage human tumors display markers of a DNA-damage response (DDR), including ataxia telangiectasia mutated (ATM) kinase activation. This suggests that DNA damage accumulates during the process of carcinogenesis and that the ATM-dependent response to this damage may function to suppress cancer progression. The E2F3a transcription factor plays an important role in regulating cell proliferation and is amplified in a subset of human cancers. Similar to human premalignant lesions, we find activated ATM and other markers of the DDR in the hyperplastic epidermis of transgenic mice expressing E2F3a through a keratin 5 (K5) promoter. Primary keratinocytes from K5 E2F3a transgenic mice contain increased levels of DNA breaks compared to wild-type cells. E2F3a overexpression also induced DNA damage in primary human fibroblasts that was inhibited by blocking DNA replication. The absence of ATM impaired apoptosis induced by E2F3a and treating K5 E2F3a transgenic mice with caffeine, an inhibitor of ATM and Rad3-related (ATR), promoted skin tumor development. These findings demonstrate that the deregulated expression of E2F3a causes DNA damage under physiological conditions and indicate that the ATM-dependent response to this damage is important for the induction of apoptosis and tumor suppression.

Accelerated DNA replication in E2F1- and E2F2-deficient macrophages leads to induction of the DNA damage response and p21CIP1-dependent senescence

“…It has been suggested that oncogenes cause DNA damage by increasing the production of reactive oxygen species, by telomere attrition, or through the vague concept of replicative stress. Our finding that aphidicolin can block the activation of DDR in E2F1/E2F2 À/À cells has some similarity to other reports implicating aberrant DNA replication in oncogene-induced DNA damage (Bartkova et al, 2006;Di Micco et al, 2006;Paulson et al, 2008). It is possible that overexpression of the replication proteins Mcm2, Mcm3 and Cdc6 in E2F1/E2F2 À/À cells shown in this study may cause DNA damage by promoting illegitimate replication origin firing, which could, in turn, result in head-to-tail fork collision and checkpoint activation, similarly to what has been shown in cell extracts overexpressing the replication protein Cdt1 (Davidson et al, 2006).…”

“…Very rarely, a pre-cancerous cell with aberrant DNA replication could evade this tumor suppressive barrier, such as by mutating p53 (Di Micco et al, 2006). Activation of the DDR is common in cells and tissues that overexpress oncogenic regulators of cellular proliferation, such as Ras, Braf, mos, cyclin E or E2F3 (Bartkova et al, 2006;Di Micco et al, 2006;Paulson et al, 2008). It has been suggested that oncogenes cause DNA damage by increasing the production of reactive oxygen species, by telomere attrition, or through the vague concept of replicative stress.…”

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

“…The pathways that were specifically enriched in adenomas in our analysis are known to be activated in colorectal carcinogenesis (causal, resulting or compensatory) such as the Wnt pathway (Midgley and Kerr, 1999), cell cycle routes (Hao et al, 1998), DNA base metabolism, transcription, ATM (Kwong et al, 2008;Paulson et al, 2008), ARF, p27 (Payne et al, 2008) and p53 (Einspahr et al, 2006) signaling routes. In addition, we found novel pathways unique to adenomas, among which are the Rb pathway, the Src pathway, folate biosynthesis and the PTC1 pathway.…”

Large T Antigen Promotes JC Virus Replication in G2-arrested Cells by Inducing ATM- and ATR-mediated G2 Checkpoint Signaling

“…Given that we obtained evidence that JCV-infected oligodendrocytes were arrested at the G 2 phase in a brain of an individual with PML, ATM-ATR inhibitors such as caffeine might prove clinically effective against JCV infection. Although it is difficult to assess the antiviral effect of caffeine at a nontoxic dose in vivo because of the lack of an animal model of JCV infection, recent studies have shown that the administration of caffeine in drinking water resulted in the inhibition of ATM or ATR signaling pathways in mice (49,50). In addition, given that it readily crosses the blood-brain barrier, caffeine is likely to have access to target cells in central nervous system diseases such as PML.…”