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
  • 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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