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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 (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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Figure 1: Loss of EYA leads to increased γ-H2AX-posititve apoptotic cells.
Figure 2: EYA interacts with H2AX in a DNA-damage-dependent manner.
Figure 3: EYA3 phosphorylation by ATM/ATR DNA-damage-dependent kinases regulates the interaction between EYA and H2AX.
Figure 4: Tyrosine phosphorylated H2AX is a substrate for EYA phosphatase.
Figure 5: H2AX Y142 phosphorylation discriminates between apoptotic and repair responses to DNA damage.


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We thank M. Kastan for providing reagents/technical assistance for the I-PpoI system. We thank V. Lunyak, J. Dixon and R. Koladner for review and discussions. We thank the laboratory of R. S. Johnson for use of equipment and advice on hypoxia incubations, as well as H. Taylor for animal care assistance and C. Nelson for cell culture assistance. We thank A. Nussenzweig, Y. Xu and H. Song for H2ax-/- MEFs. We thank J. Hightower and M. Fisher for assistance with figure and manuscript preparation. We additionally thank X. Li and W. Liu. M.G.R. is an HHMI Investigator. This work was supported by grants from NIH and NCI to M.G.R. and C.K.G. This work also was supported by the Sogang University Research Grant of 2008 to B.G.J and PCF and USAMRAA grants to M.G.R.

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Correspondence to Michael G. Rosenfeld.

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Cook, P., Ju, B., Telese, F. et al. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458, 591–596 (2009).

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