Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis
Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis
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基因毒性应激触发的β-连环蛋白/JDP2/PRMT5复合物有助于重建谷胱甘肽稳态
DOI：
10.1038/s41467-019-11696-7
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发表时间：
2019-08-21
影响因子：
16.6
通讯作者：
Li, Jun
中科院分区：
文献类型：
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作者：
Cao, Lixue;Wu, Geyan;Li, Jun
基因毒性应激下细胞如何重建还原-氧化（氧化还原）稳态，以维持细胞过程和细胞存活的生理功能，其机制尚不清楚。在此，我们报告，通过TCF独立的机制，基因毒性应激诱导β-连环蛋白在染色质中的富集，在那里它与ATM磷酸化-JDP 2和PRMT 5形成复合物。这表明组蛋白H3 R2 me 1/H3 R2 me 2s通过募集WDR 5/MLL甲基转移酶复合物和伴随的GSH代谢级联中多个基因启动子处的H3 K4甲基化来诱导转录激活。用OICR-9429（一种WDR 5-MLL相互作用的小分子拮抗剂）处理抑制β-连环蛋白/JDP 2/PRMT 5复合物重建的GSH代谢，导致基因毒性剂处理的癌细胞中已经升高的ROS水平的致死性增加。因此，我们的研究结果揭示了β-连环蛋白在基因毒性应激后重建氧化还原稳态中的合理作用，并揭示了癌症诱导化疗耐药的机制。
The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of beta-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the beta-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for beta-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.