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. While the regulatory mechanisms and signaling 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 specific tissue/cell types by executing a damage-signal dependent dephosphorylation of an H2AX C-terminal tyrosine phosphate (Y142). This post-translational modification determines the relative recruitment of either DNA repair or pro-apoptotic factors to the tail of γH2AX 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.