The induction of apoptosis by the E2F1 transcription factor and the emergence of a role for E2F1 in the DNA double strand break response

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Powers, John Thomas

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The E2F1 transcription factor plays an important role in cell cycle progression, largely facilitated by its ability to transcriptionally induce genes involved in cell cycle regulation and DNA replication. E2F1 also has a well documented ability to promote apoptosis in vitro and in vivo, both as a potent inducer and as a mediator. The mechanism by which E2F1 ultimately induces apoptosis has remained elusive, however. Persistent dogma suggests that the p19ARF tumor suppressor, which plays an important role in p53 stabilization and is transcriptionally regulated by E2F1, is the critical mediator of E2F1’s apoptotic capacity. Counter to this hypothesis, data presented here establish that p19ARF is not required for E2F1 to induce apoptosis. Additionally, E2F1 is observed to induce the stabilization and phosphorylation of p53 in a p19ARF independent manner. v This observation led to the discovery that the DNA damage responsive Ataxiatelangiectasia mutated kinase (ATM) is required for E2F1 to induce both p53 phosphorylation and apoptosis. A similar requirement by E2F1 exists for the Nijmegen breakage syndrome protein (NBS1), a component of the Mre11-Rad50-NBS1 (MRN) DNA repair complex and part of the ATM signaling pathway. Despite the ATM signaling pathway being defined as DNA damage responsive, no evidence of E2F1 induction of DNA damage has been observed. Moreover, E2F1 is observed to induce p53 phosphorylation in the absence of both transcription/translation and damaged DNA. Previous work has shown that E2F1 is phosphorylated by ATM in response to DNA damage and that E2F1 associates with NBS1. E2F1 also physically associates with ATM in response to several DNA damaging agents and localizes to discrete foci in response to DNA damage in an ATM and NBS1-dependent manner. Finally, E2F1 deficiency results in reduced phosphorylation of ATM, NBS1, and p53 in response to γ-irradiation. These findings demonstrate that E2F1 associates with key DNA damage-responsive proteins and may play a specific role in the DNA damage response. Such data further suggest that E2F1 induced apoptosis may be both independent of its transcriptional capacity and an extension of a physiologic role in response to DNA damage.