Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions

PJ Cook, BG Ju, F Telese, X Wang, CK Glass… - Nature, 2009 - nature.com
PJ Cook, BG Ju, F Telese, X Wang, CK Glass, MG Rosenfeld
Nature, 2009nature.com
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 …
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 (γ-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.
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