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Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.

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.

Pubmed ID: 19234442

Authors

  • Cook PJ
  • Ju BG
  • Telese F
  • Wang X
  • Glass CK
  • Rosenfeld MG

Journal

Nature

Publication Data

April 2, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA097134
  • Agency: NCI NIH HHS, Id: R01 CA097134-06A1
  • Agency: NCI NIH HHS, Id: R01 CA097134-07
  • Agency: NIDDK NIH HHS, Id: R01 DK039949
  • Agency: NIDDK NIH HHS, Id: R01 DK039949-17S1
  • Agency: NIDDK NIH HHS, Id: R01 DK039949-18
  • Agency: NHLBI NIH HHS, Id: R01 HL065445
  • Agency: NHLBI NIH HHS, Id: R01 HL065445-08
  • Agency: NHLBI NIH HHS, Id: R01 HL065445-09
  • Agency: NINDS NIH HHS, Id: R01 NS034934
  • Agency: NINDS NIH HHS, Id: R01 NS034934-18
  • Agency: NINDS NIH HHS, Id: R01 NS034934-19
  • Agency: NINDS NIH HHS, Id: R01 NS034934-20A1
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

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