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Genotoxic stress-triggered ?-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis.


ABSTRACT: 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 ?-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 ?-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 ?-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.

SUBMITTER: Cao L 

PROVIDER: S-EPMC6704105 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis.

Cao Lixue L   Wu Geyan G   Zhu Jinrong J   Tan Zhanyao Z   Shi Dongni D   Wu Xingui X   Tang Miaoling M   Li Ziwen Z   Hu Yameng Y   Zhang Shuxia S   Yu Ruyuan R   Mo Shuang S   Wu Jueheng J   Song Erwei E   Li Mengfeng M   Song Libing L   Li Jun J  

Nature communications 20190821 1


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 β-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2  ...[more]

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