Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair.
Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair.
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DOI：
10.1038/ncomms6691
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发表时间：
2014-12-09
影响因子：
16.6
通讯作者：
Hamamoto, Ryuji
中科院分区：
文献类型：
--
作者：
Sone, Kenbun;Piao, Lianhua;Nakakido, Makoto;Ueda, Koji;Jenuwein, Thomas;Nakamura, Yusuke;Hamamoto, Ryuji
磷酸化组蛋白H2 AX（γ-H2 AX）的存在与DNA损伤修复途径的局部激活有关。尽管先前已经报道了γ-H2 AX在癌症中的失调，但所涉及的分子机制及其与其他组蛋白修饰的关系在很大程度上仍然未知。在这里，我们发现组蛋白甲基转移酶SUV 39 H2甲基化赖氨酸134上的组蛋白H2 AX。当H2 AX突变以消除K134甲基化时，γ-H2 AX的水平变得显著降低。我们还发现在Suv 39 H2敲除细胞中引入双链断裂后或在SUV 39 H2敲减后γ-H2 AX活性较低。临床肺和膀胱组织的组织微阵列分析也揭示了H2 AX K134甲基化和γ-H2 AX水平之间的正相关性。此外，K134取代的组蛋白H2 AX的引入增强了癌细胞的放射和化学敏感性。总的来说，我们的研究结果表明，H2 AX甲基化在癌症中γ-H2 AX丰度的调节中起作用。 γ-H2 AX是H2 AX的丝氨酸139磷酸化形式，γ-H2 AX是响应DNA双链断裂而产生的，并参与修复过程。Sone等人的研究表明，SUV 39 H2引起的H2 AX K134甲基化对γ-H2 AX的产生至关重要，甲基化的丧失与放射敏感性和化学敏感性相关。
The presence of phosphorylated histone H2AX (γ-H2AX) is associated with the local activation of DNA-damage repair pathways. Although γ-H2AX deregulation in cancer has previously been reported, the molecular mechanism involved and its relationship with other histone modifications remain largely unknown. Here we find that the histone methyltransferase SUV39H2 methylates histone H2AX on lysine 134. When H2AX was mutated to abolish K134 methylation, the level of γ-H2AX became significantly reduced. We also found lower γ-H2AX activity following the introduction of double-strand breaks in Suv39h2 knockout cells or on SUV39H2 knockdown. Tissue microarray analyses of clinical lung and bladder tissues also revealed a positive correlation between H2AX K134 methylation and γ-H2AX levels. Furthermore, introduction of K134-substituted histone H2AX enhanced radio- and chemosensitivity of cancer cells. Overall, our results suggest that H2AX methylation plays a role in the regulation of γ-H2AX abundance in cancer. γ-H2AX The Ser139 phosphorylated form of H2AX, γ-H2AX, is generated in response to DNA double-strand breaks and is involved in the repair process. Here, Sone et al. show that H2AX K134 methylation by SUV39H2 is crucial for the production of γ-H2AX, and that loss of methylation correlates with radio- and chemosensitivity.
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