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The mef/elf4 transcription factor fine tunes the DNA damage response.

ABSTRACT: 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 ?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 ?H2AX foci in response to ?-irradiation, leading to a radio-resistant phenotype despite normal ATM phosphorylation. Following ?-irradiation, ATM phosphorylates ELF4, leading to its degradation; a mutant form of ELF4 that cannot be phosphorylated by ATM persists following ?-irradiation, delaying the resolution of ?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.

SUBMITTER: Sashida G

PROVIDER: S-EPMC4073677 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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The mef/elf4 transcription factor fine tunes the DNA damage response.

Sashida Goro G Bae Narae N Di Giandomenico Silvana S Asai Takashi T Gurvich Nadia N Bazzoli Elena E Liu Yan Y Huang Gang G Zhao Xinyang X Menendez Silvia S Nimer Stephen D SD

Cancer research 20110526 14

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 γH2AX 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 γH2AX foci in respo ...[more]

PMID: 21616937

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Project description:BackgroundInflammatory response after myocardial infarction (MI) is essential for cardiac healing, whereas excessive and prolonged inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanistic insight of these tightly controlled inflammatory processes has a significant impact on post-MI recovery and therapy. Here, we uncover the critical role of small GTPase RhoE in post-MI recovery and its clinical implication.MethodsThree genetic mouse lines are used: global RhoE knockout, cardiomyocyte-specific RhoE heterozygous, and cardiomyocyte-specific RhoE overexpression mice. A set of molecular signaling experiments, including bimolecular fluorescence complementation, immunoprecipitation, electrophoretic mobility shift assay, and mRNA microarray analysis, were conducted. Permanent ligation of the left anterior descending artery was performed, followed by the assessments of cardiac function, inflammation, and survival in the first week after MI. Finally, we examined the correlation of the expression levels of RhoE in MI patient heart and patient prognosis.ResultsRhoE deficiency turns on a group of proinflammatory gene expressions in mouse heart. Mice with cardiomyocyte-specific haploinsufficiency exhibit excessive inflammatory response with deleterious cardiac function after MI. A profound increase in nuclear factor-κB activity is detected in the mutant heart and the isolated cardiomyocytes. We further find that the expression of RhoE is upregulated in response to MI. Mechanistically, RhoE interacts with p65 and p50 individually in cytosol and blocks their nuclear translocation. RhoE also occupies the dimerization domain of p65 and subsequently disrupts the heterodimerization between p65 and p50. Cardiac RhoE overexpression inhibits nuclear factor-κB activity, restrains post-MI inflammation, and improves cardiac function and survival. Consistently, we find that the expression level of RhoE is elevated in the heart of patients with MI and that the patients with a higher expression level of RhoE exhibit a better prognosis in cardiac function recovery.ConclusionsThe study uncovers RhoE as a new fine-tuning factor modulating MI-induced inflammation and promoting injured heart recovery. RhoE may serve as a new potential biomarker for the assessment of MI patient prognosis. Manipulation of RhoE could be as a potential therapeutic approach for MI and other inflammatory diseases.

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The mef/elf4 transcription factor fine tunes the DNA damage response.

Publications

The mef/elf4 transcription factor fine tunes the DNA damage response.

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