The Mef/Elf4 Transcription Factor Fine Tunes the DNA Damage Response

The ATM kinase plays a critical role in initiating the DNA damage response that is triggered by genotoxic stresses capable of inducing DNA double-strand breaks. Here, we show that ELF4/MEF, a member of the ETS family of transcription factors, contributes to the persistence of gamma H2AX DNA damage foci and promotes the DNA damage response leading to the induction of apoptosis. Conversely, the absence of ELF4 promotes the faster repair of damaged DNA and more rapid disappearance of gamma H2AX foci in response to gamma-irradiation, leading to a radio-resistant phenotype despite normal ATM phosphorylation. Following gamma-irradiation, ATM phosphorylates ELF4, leading to its degradation; a mutant form of ELF4 that cannot be phosphorylated by ATM persists following gamma-irradiation, delaying the resolution of gamma H2AX foci and triggering an excessive DNA damage response. Thus, although ELF4 promotes the phosphorylation of H2AX by ATM, its activity must be dampened by ATM-dependent phosphorylation and degradation to avoid an excessive DNA damage response. Cancer Res; 71(14); 4857-65. (C) 2011 AACR.