Sone Kenbun, Piao Lianhua, Nakakido Makoto, Ueda Koji, Jenuwein Thomas, Nakamura Yusuke, Hamamoto Ryuji
Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA.
Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Nat Commun. 2014 Dec 9;5:5691. doi: 10.1038/ncomms6691.
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.
磷酸化组蛋白H2AX（γ-H2AX）的存在与DNA损伤修复途径的局部激活相关。尽管此前已有关于癌症中γ-H2AX失调的报道，但其中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不清楚。在此，我们发现组蛋白甲基转移酶SUV39H2使组蛋白H2AX的赖氨酸134位点发生甲基化。当H2AX发生突变以消除K134甲基化时，γ-H2AX的水平显著降低。我们还发现在Suv39h2基因敲除细胞中引入双链断裂后或在SUV39H2基因敲低后，γ-H2AX活性降低。对临床肺组织和膀胱组织的组织芯片分析也显示H2AX K134甲基化与γ-H2AX水平之间呈正相关。此外，引入K134取代的组蛋白H2AX可增强癌细胞的放射敏感性和化学敏感性。总体而言，我们的结果表明H2AX甲基化在癌症中γ-H2AX丰度的调节中发挥作用。
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