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Abstract
Protein methyltransferases regulate gene expression, chromatin structure, and signaling pathways through site-specific methylation of lysine and arginine residues. PRMT1 is responsible for the majority of arginine methylation in mammalian cells and functions not only through its catalytic activity but also via protein–protein interactions. PRMT6 was identified as a novel substrate of PRMT1, and PRMT1-mediated methylation at R106 suppresses PRMT6 enzymatic activity, suggesting an inhibitory regulatory mechanism within the PRMT family. In addition, PRMT1 enhances SETD8-mediated H4K20 monomethylation through a non-catalytic mechanism, as shown by both overexpression and inhibitor-based experiments, pointing to a scaffolding or structural role. This enhancement is specific to the nucleosome context and is not observed with free histone peptides. Functional assays further demonstrate that PRMT1 and SETD8 co-localize and interact indirectly, likely through multi-protein complexes. To expand the study of methyltransferase regulation to viral systems, the SARS-CoV-2 2′-O-methyltransferase NSP16 was investigated as a target for inhibitor discovery. A scintillation proximity assay was developed and optimized for NSP16 enzymatic activity, and molecular docking-based virtual screening was combined with biochemical validation to identify small-molecule inhibitors. These findings provide new insights into both the regulatory dynamics of human methyltransferases and strategies for targeting viral methyltransferases in antiviral drug development.