Arginine methylation of APE1 promotes its mitochondrial translocation to protect cells from oxidative damage

• Published in: Free radical biology & medicine Vol. 158; pp. 60 - 73
• Main Authors: Zhang, Yilan, Zhang, Qi, Li, LuLu, Mu, Dan, Hua, Ke, Ci, Shusheng, Shen, Lei, Zheng, Li, Shen, Binghui, Guo, Zhigang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2020
• Subjects: Animals; APE1; Arginine; Arginine methylation; DNA Damage; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Endonucleases; HEK293 Cells; Humans; Methylation; Mitochondria; Oxidative Stress; Post-translational modification; PRMT1; Protein Processing, Post-Translational; Protein-Arginine N-Methyltransferases - genetics; Repressor Proteins; Post-translational modification; SDMA; Tom20; APE1; PRMT1; F; PTM; ADMA; BER; Arginine methylation; Mitochondria; THF; ROS
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2020.06.027

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential multifunctional protein in mammals that plays critical roles in DNA repair and redox signaling within the cell. Impaired APE1 function or dysregulation is associated with disease susceptibility and poor cancer prognosis. Orchestrated regulatory mechanisms are crucial to ensure its function in a specific subcellular location at specific time. Here, we report arginine methylation as a post-translational modification (PTM) that regulates APE1 translocation to mitochondria in HeLa and HEK-293 cells. Protein arginine methyl-transferase 1 (PRMT1) was shown to methylate APE1 in vitro. Site-directed mutagenesis identified R301 as the major methylation site. We confirmed that APE1 is methylated in cells and that the R301K mutation significantly reduces its methylation. Baseline mitochondrial APE1 levels were low under standard culture conditions, but they could be induced by oxidative agents. Methylation-deficient APE1 showed reduced mitochondrial translocation. Methylation affected the interaction of APE1 with Tom20, translocase of the outer mitochondrial membrane. Methylation-deficient APE1 resulted in increased mitochondrial DNA damage and increased cytochrome c release after stimuli. These data suggest that methylation of APE1 promotes its mitochondrial translocation and protects cells from oxidative damage. This work describes a novel PTM regulation model of APE1 subcellular distribution through arginine methylation.
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•APE1 is methylated by PRMT1 at R301.•Oxidative agent (H2O2 or menadione) treatment induces arginine methylation and mitochondrial translocation of APE1.•R301 methylation of APE1 promotes its interaction with Tom20.•APE1 arginine methylation deficiency sensitizes cells to oxidative damage.