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

Free Radical Biology & Medicine
Yilan ZhangZhigang Guo

Abstract

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 afte...Continue Reading

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Citations

Dec 16, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Yu ZhangPingsheng Chen
Jul 3, 2021·International Journal of Molecular Sciences·David J LópezSonia Bañuelos
May 7, 2021·Endocrine Reviews·Lucie MalbeteauMuriel Le Romancer

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