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

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential multifunctional protein in mammals that plays critical roles in DNA base excision repair and redox signaling within the cell. Impaired APE1 function or dysregulation is associated with disease susceptibility, cancer progression and poor prognosis. Orchestrated regulatory mechanisms are crucial to ensure its function in specific subcellular location, at a specific time. 

Recently, Professor Zhigang Guo from Nanjing Normal University, published their latest work on APE1 at Free Radical Biology & Medicine, titled “Arginine methylation of APE1 promotes its mitochondrial translocation to protect cells from oxidative damage”. They are the first to report arginine methylation of APE1, adding to APE1 post-translational modification (PTM) regulation network. It would provide some scientific evidence for targeting APE1 as diagnostic marker and individualized medicine.

Protein arginine methyl-transferase 1 (PRMT1) was shown to methylate APE1 in vitro. Site-directed mutagenesis identified R301 as the major methylation site. Methylation-deficient APE1 (R301K) showed reduced mitochondrial translocation compared to wild-type or methylation-mimic APE1. R301K APE1 KI resulted in increased mitochondrial DNA damage and increased cytochrome c release after stimuli. Wild-type or R301F mutation APE1 could partially rescue methylation deficiency caused phenotype. 

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, complementing APE1 PTM network. Arginine methylation specific antibody could be designed as a potential adjuvant in individualized therapeutics.   

Dr. Yilan Zhang, Nanjing Normal University, is the first author of this paper. Professor Zhigang Guo and Professor Binghui Shen (City of Hope, Beckman Research Institute, US) are correspondence authors.