Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions

Nature. 2009 Apr 2;458(7238):591-6. doi: 10.1038/nature07849. Epub 2009 Feb 22.

Abstract

Life and death fate decisions allow cells to avoid massive apoptotic death in response to genotoxic stress. Although the regulatory mechanisms and signalling pathways controlling DNA repair and apoptosis are well characterized, the precise molecular strategies that determine the ultimate choice of DNA repair and survival or apoptotic cell death remain incompletely understood. Here we report that a protein tyrosine phosphatase, EYA, is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in mammalian embryonic kidney cells by executing a damage-signal-dependent dephosphorylation of an H2AX carboxy-terminal tyrosine phosphate (Y142). This post-translational modification determines the relative recruitment of either DNA repair or pro-apoptotic factors to the tail of serine phosphorylated histone H2AX (gamma-H2AX) and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Survival
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Histones / deficiency
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Protein Tyrosine Phosphatases / deficiency
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Substrate Specificity
  • Tumor Suppressor Proteins / metabolism
  • Tyrosine / metabolism*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • H2AX protein, human
  • H2AX protein, mouse
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • Phosphotyrosine
  • Tyrosine
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • EYA1 protein, human
  • EYA3 protein, human
  • Eya1 protein, mouse
  • Protein Tyrosine Phosphatases