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Quantification of γH2AX Foci in Response to Ionising Radiation
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Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions

Peter J Cook1, Bong Gun Ju, Francesca Telese

  • 1Howard Hughes Medical Institute School of Medicine, University of California, San Diego, California 92037, USA.

Nature
|February 24, 2009
PubMed

Insights

Protein tyrosine phosphatase EYA promotes DNA repair over apoptosis after genotoxic stress. It dephosphorylates histone H2AX (Y142), influencing cell fate decisions during mammalian organogenesis.

Area of Science:

  • Cellular biology
  • Molecular biology
  • Genetics

Background:

  • Cellular fate decisions, such as apoptosis or survival, are critical responses to genotoxic stress.
  • While DNA repair and apoptosis pathways are known, the molecular mechanisms determining cell fate remain unclear.
  • Histone modifications, like phosphorylation of H2AX (gamma-H2AX), are key markers of DNA damage.

Purpose of the Study:

  • To investigate the molecular mechanisms controlling cell fate decisions following genotoxic stress.
  • To identify novel regulators involved in the balance between DNA repair and apoptosis.
  • To elucidate the role of protein tyrosine phosphatase EYA in response to DNA damage.

Main Methods:

  • Utilized mammalian embryonic kidney cells.
  • Investigated the role of protein tyrosine phosphatase EYA in response to genotoxic stress.
  • Analyzed damage-signal-dependent dephosphorylation of H2AX at Y142.
  • Assessed recruitment of DNA repair and pro-apoptotic factors to gamma-H2AX.

Main Results:

  • Protein tyrosine phosphatase EYA promotes DNA repair and suppresses apoptosis following genotoxic stress.
  • EYA executes a damage-signal-dependent dephosphorylation of H2AX at Y142.
  • This dephosphorylation influences the recruitment of DNA repair or pro-apoptotic factors to gamma-H2AX.
  • H2AX phosphorylation state acts as a determinant of repair/survival versus apoptotic outcomes.

Conclusions:

  • EYA plays a crucial role in modulating cell fate decisions after DNA damage.
  • Dephosphorylation of H2AX (Y142) by EYA is a key post-translational modification determining cell survival or apoptosis.
  • This mechanism reveals a novel phosphorylation-dependent pathway regulating cell fate during mammalian organogenesis.

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