Redox Control of Protein Arginine Methyltransferase 1 (PRMT1) Activity

Abstract

Elevated levels of asymmetric dimethylarginine (ADMA) correlate with risk factors for cardiovascular disease. ADMA is generated by the catabolism of proteins methylated on arginine residues by protein arginine methyltransferases (PRMTs), and is degraded by dimethylarginine dimethylaminohydrolase (DDAH). Reports have shown that DDAH activity is down regulated and PRMT1 protein expression is upregulated under oxidative stress conditions, leading many to conclude that ADMA accumulation occurs via increased synthesis by PRMTs and decreased degradation. However, we now report that the methyltransferase activity of PRMT1, the major PRMT isoform in humans, is impaired under oxidative conditions. Oxidized PRMT1 displays decreased activity, which can be rescued by reduction. Mutagenesis studies demonstrate that the oxidation event involves two cysteine residues on PRMT1. We demonstrate a hydrogen peroxide concentration‐dependent inhibition of PRMT1 activity that is readily reversed under physiological H2O2 concentrations. We additionally show that PRMT1 purified from oxidatively challenged human cells displays impaired activity compared to PRMT1 purified from healthy human cells. Our results challenge the unilateral view that increased PRMT1 expression necessarily results in increased ADMA synthesis, but rather demonstrate that enzymatic activity can be regulated in a redox‐sensitive manner. Our findings suggest that modulation of protein arginine methylation could play a large role in the oxidative stress response.