title: Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.
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.
authors.affiliation: Howard Hughes Medical Institute School of Medicine, University of California, San Diego, California 92037, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cook
authors.forename: Bong Gun
authors.initials: BG
authors.lastname: Ju
authors.forename: Francesca
authors.initials: F
authors.lastname: Telese
authors.forename: Xiangting
authors.initials: X
authors.lastname: Wang
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D019000:Phosphotyrosine; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D025521:Tumor Suppressor Proteins; D014443:Tyrosine; C468783:H2AX protein, human; C576324:ATM protein, human; C576597:ATR protein, human; C576325:Atm protein, mouse; C104381:EYA1 protein, human; C540714:EYA3 protein, human; C501156:Eya1 protein, mouse; C475961:gamma-H2AX protein, mouse