Tyrosine Dephosphorylation of H2AX Modulates Apoptosis and Survival Decisions

Howard Hughes Medical Institute School of Medicine, University of California, San Diego, California 92037, USA.
Nature (Impact Factor: 41.46). 02/2009; 458(7238):591-596. DOI: 10.1038/nature07849


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 (-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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    • "Since the regulation of H2AX phosphorylation (Ser 139 and Tyr 142) is crucial to somatic DDR (Cook et al., 2009), we initially sought to examine the functional relationship between these two sites in the germline where DDR events occur in the context of normal developmental processes. To this end, we focused on BAZ1B, the sole known enzyme that mediates Tyr142 phosphorylation of H2AX (pTyr142) in somatic cells (Xiao et al., 2009). "
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    ABSTRACT: Meiosis is precisely regulated by the factors involved in DNA damage response in somatic cells. Among them, phosphorylation of H2AX on Serine 139 (γH2AX) is an essential signal for the silencing of unsynapsed sex chromosomes during male meiosis. However, it remains unknown how adjacent H2AX phosphorylation on Tyrosine 142 (pTyr142) is regulated in meiosis. Here we investigate the meiotic functions of BAZ1B (WSTF), the only known Tyr142 kinase in somatic cells, using mice possessing a conditional deletion of BAZ1B. Although BAZ1B deletion causes ectopic γH2AX signals on synapsed autosomes during the early pachytene stage, BAZ1B is dispensable for fertility and critical events during spermatogenesis. BAZ1B deletion does not alter events on unsynapsed axes and pericentric heterochromatin formation. Furthermore, BAZ1B is dispensable for localization of the ATP-dependent chromatin remodeling protein SMARCA5 (SNF2h) during spermatogenesis despite the complex formation between BAZ1B and SMARCA5, known as the WICH complex, in somatic cells. Notably, pTyr142 is regulated independently of BAZ1B and is dephosphorylated on the sex chromosomes during meiosis in contrast with the presence of adjacent γH2AX. Dephosphorylation of pTyr142 is regulated by MDC1, a binding partner of γH2AX. These results reveal the distinct regulation of two adjacent phosphorylation sites of H2AX during meiosis, and suggest that another kinase mediates Tyr142 phosphorylation. © 2015. Published by The Company of Biologists Ltd.
    Biology Open 05/2015; 4(7). DOI:10.1242/bio.011734 · 2.42 Impact Factor
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    • "Thus, an increased capacity of DNA damage repair in tumor cells is thought to be an important contributor to chemotherapeutic resistance during cancer treatments 36. Phosphorylation of γH2A.X was recently reported to serve as an apoptotic induction signal 37. These data suggest that DNA damage-induced apoptosis may contribute to the effects of AKR1C3 silencing in enhancing MTX sensitivity. "
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    ABSTRACT: Background: Chemotherapy is typically used to treat choriocarcinoma, but a small proportion of tumors develop resistance to chemotherapy. Similarly, methotrexate (MTX) is a first-line chemotherapy used to treat choriocarcinoma; although ~30% of patients are drug-resistant for MTX mono-therapy. Thus, we sought to elucidate the mechanism of chemotherapeutic-resistance of MTX. Methods: RNA interference technology, colony formation, and MTT assays were used to investigate the role of aldo-keto reductase family 1, member C3 (AKR1C3) in MTX resistance in choriocarcinoma cells. Results: AKR1C3 expression was higher in JeG-3R cells compared to JeG-3 cells and targeted inhibition of AKR1C3 expression with shRNA suppresses growth of choriocarcinoma cells as measured by colony formation and MTT assays. Overexpression of AKR1C3 increased chemotherapeutic resistance in JeG-3 cells. Furthermore, AKR1C3 silencing increases sensitivity to MTX in JeG-3R choriocarcinoma cells. Increasing MTX sensitivity spears to be related to DNA damage induction by increased reactive oxygen species (ROS), apoptosis, and cell cycle arrest. Conclusions: Data show that AKR1C3 is critical to the development of methotrexate resistance in choriocarcinoma and suggest that AKR1C3 may potentially serve as a therapeutic marker for this disease.
    International journal of medical sciences 08/2014; 11(11):1089-1097. DOI:10.7150/ijms.9239 · 2.00 Impact Factor
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    • "Under basal conditions Y142 is constitutively phosphorylated by the WSTF (Williams syndrome transcription factor) kinase. In response to DSBs, H2A.X becomes phosphorylated at S139 and progressively dephosphorylated at Y142 by Eya1 and Eya3 tyrosine phosphatases enabling MDC1 binding [102]. Elegant biochemical and structural studies have provided insight into mechanistic aspects of the recognition of those differential phosphorylation patterns by effector proteins. "
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    ABSTRACT: Systematic analysis of histone modifications has revealed a plethora of posttranslational modifications that mediate changes in chromatin structure and gene expression. Histone phosphorylation is a transient histone modification that becomes induced by extracellular signals, DNA damage or entry into mitosis. Importantly, phosphorylation of histone proteins does not only lead to the binding of specific reader proteins but also to changes in the affinity for readers or writers of other histone modifications. This induces a cross-talk between different chromatin modifications that allows the spatio-temporal control of chromatin-associated events. In this review we will summarize the progress in our current knowledge of factors sensing reversible histone phosphorylation in different biological scenarios. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.
    Biochimica et Biophysica Acta 04/2014; 1839(8). DOI:10.1016/j.bbagrm.2014.04.013 · 4.66 Impact Factor
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