DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity.
DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity.
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DNA-PK 介导的 EZH2 磷酸化调节 DNA 损伤诱导的细胞凋亡以维持 T 细胞基因组完整性
DOI：
10.1038/cddis.2016.198
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发表时间：
2016-07-28
影响因子：
9
通讯作者：
Zhu T
中科院分区：
文献类型：
--
作者：
Wang Y;Sun H;Wang J;Wang H;Meng L;Xu C;Jin M;Wang B;Zhang Y;Zhang Y;Zhu T
EZH 2是一种组蛋白甲基转移酶，其在干细胞和肿瘤细胞中的功能已得到充分证实。越来越多的证据表明，EZH 2在T细胞中具有关键作用，可能是多种免疫疾病的有希望的治疗靶点。为了进一步揭示EZH 2在人类T细胞中的新功能，进行了蛋白质免疫共沉淀结合质谱分析，并鉴定了几种先前未知的EZH 2相互作用蛋白。其中，我们专注于DNA损伤反应蛋白Ku 80，因为对DNA损伤反应中EZH 2的了解有限。然后，我们证明Ku 80不是被EZH 2甲基化，而是桥接DNA依赖性蛋白激酶（DNA-PK）复合物和EZH 2之间的相互作用，从而促进EZH 2磷酸化。此外，当Ku 80被敲低或DNA-PK活性被抑制时，EZH 2组蛋白甲基转移酶活性增强，表明DNA-PK介导的EZH 2磷酸化损害EZH 2组蛋白甲基转移酶活性。另一方面，EZH 2抑制增加了T细胞活化晚期的DNA损伤水平，表明EZH 2参与基因组完整性的维持。总之，我们的研究首次证明EZH 2被DNA损伤应答复合物DNA-PK磷酸化，并调节DNA损伤介导的T细胞凋亡，这揭示了表观遗传调控和基因组完整性之间的新功能串扰。
EZH2 is a histone methyltransferase whose functions in stem cells and tumor cells are well established. Accumulating evidence shows that EZH2 has critical roles in T cells and could be a promising therapeutic target for several immune diseases. To further reveal the novel functions of EZH2 in human T cells, protein co-immunoprecipitation combined mass spectrometry was conducted and several previous unknown EZH2-interacting proteins were identified. Of them, we focused on a DNA damage responsive protein, Ku80, because of the limited knowledge regarding EZH2 in the DNA damage response. Then, we demonstrated that instead of being methylated by EZH2, Ku80 bridges the interaction between the DNA-dependent protein kinase (DNA-PK) complex and EZH2, thus facilitating EZH2 phosphorylation. Moreover, EZH2 histone methyltransferase activity was enhanced when Ku80 was knocked down or DNA-PK activity was inhibited, suggesting DNA-PK-mediated EZH2 phosphorylation impairs EZH2 histone methyltransferase activity. On the other hand, EZH2 inhibition increased the DNA damage level at the late phase of T-cell activation, suggesting EZH2 involved in genomic integrity maintenance. In conclusion, our study is the first to demonstrate that EZH2 is phosphorylated by the DNA damage responsive complex DNA-PK and regulates DNA damage-mediated T-cell apoptosis, which reveals a novel functional crosstalk between epigenetic regulation and genomic integrity.