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

Cancer Res. 2011 Jul 15;71(14):4857-65. doi: 10.1158/0008-5472.CAN-11-0455. Epub 2011 May 26.

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 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 response to γ-irradiation, leading to a radio-resistant phenotype despite normal ATM phosphorylation. Following γ-irradiation, ATM phosphorylates ELF4, leading to its degradation; a mutant form of ELF4 that cannot be phosphorylated by ATM persists following γ-irradiation, delaying the resolution of γH2AX 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • DNA / genetics
  • DNA / metabolism
  • DNA / radiation effects
  • DNA Breaks, Double-Stranded*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / radiation effects
  • Enzyme Activation
  • Gamma Rays
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Phosphorylation / radiation effects
  • Protein Serine-Threonine Kinases / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / radiation effects
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Elf4 protein, mouse
  • Histones
  • Transcription Factors
  • Tumor Suppressor Proteins
  • gamma-H2AX protein, mouse
  • DNA
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases