2. Academic Validation
  3. Genotoxic stress-triggered β-catenin/JDP2/PRMT5 complex facilitates reestablishing glutathione homeostasis

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

  • Nat Commun. 2019 Aug 21;10(1):3761. doi: 10.1038/s41467-019-11696-7.
Lixue Cao 1 2,  Geyan Wu 1 3,  Jinrong Zhu 1 2,  Zhanyao Tan 2,  Dongni Shi 3,  Xingui Wu 2,  Miaoling Tang 3,  Ziwen Li 2,  Yameng Hu 2,  Shuxia Zhang 2,  Ruyuan Yu 2,  Shuang Mo 2,  Jueheng Wu 4,  Erwei Song 5,  Mengfeng Li 4,  Libing Song 3,  Jun Li 6 7
Affiliations

Affiliations

  • 1 Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou, China.
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 5 Department of Breast Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 6 Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 7 Department of Biochemistry, Zhongshan school of medicine, Sun Yat-sen University, Guangzhou, China. [email protected].
PMID: 31434880 DOI: 10.1038/s41467-019-11696-7
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.

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