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

Lixue Cao, Geyan Wu, Jinrong Zhu, Zhanyao Tan, Dongni Shi, Xingui Wu, Miaoling Tang, Ziwen Li, Yameng Hu, Shuxia Zhang, Ruyuan Yu, Shuang Mo, Jueheng Wu, Erwei Song, Mengfeng Li, Libing Song and Jun Li ()
Additional contact information
Lixue Cao: Sun Yat-sen University
Geyan Wu: Sun Yat-sen University
Jinrong Zhu: Sun Yat-sen University
Zhanyao Tan: Sun Yat-sen University
Dongni Shi: Sun Yat-sen University Cancer Center
Xingui Wu: Sun Yat-sen University
Miaoling Tang: Sun Yat-sen University Cancer Center
Ziwen Li: Sun Yat-sen University
Yameng Hu: Sun Yat-sen University
Shuxia Zhang: Sun Yat-sen University
Ruyuan Yu: Sun Yat-sen University
Shuang Mo: Sun Yat-sen University
Jueheng Wu: Sun Yat-sen University
Erwei Song: Sun Yat-Sen University
Mengfeng Li: Sun Yat-sen University
Libing Song: Sun Yat-sen University Cancer Center
Jun Li: Sun Yat-sen University

Nature Communications, 2019, vol. 10, issue 1, 1-17

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

Date: 2019
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DOI: 10.1038/s41467-019-11696-7

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