| PRMT6 is a type I protein arginine methyltransferase of the PRMT family that localizes predominantly to the nucleus, where it transfers methyl groups from S‑adenosylmethionine to arginine residues on histones and nonhistone proteins to control chromatin structure, gene expression, and signaling outputs in proliferating cells and diverse tumor types. The enzyme contains the canonical PRMT catalytic core with a Rossmann‑like fold and conserved THW and double‑E motifs that position the arginine substrate and cofactor, and this architecture supports asymmetric dimethylation of arginine side chains on histone H3 as well as multiple regulatory proteins. PRMT6 deposits a repressive H3R2me2a mark at promoters and enhancers, which antagonizes H3K4 methylation and reduces transcriptional activation of select tumor suppressor and cell‑cycle inhibitor genes, aligning its chromatin activity with maintenance of a proliferative transcriptional program. PRMT6 also methylates several signaling and cell‑cycle regulators, including the CDK inhibitor p21 and the lipid phosphatase PTEN, and these modifications alter their localization, stability, and pathway coupling. Arginine methylation of p21 at a defined C‑terminal site promotes phosphorylation on a neighboring threonine residue, increases retention of p21 in the cytoplasm, and is associated with stronger CDK2–cyclin E activity and reduced nuclear CDK inhibition, thereby favoring DNA synthesis and resistance to cytotoxic agents. Arginine methylation of PTEN on specific residues by PRMT6 decreases PI3K–AKT pathway activity and also influences pre‑mRNA splicing patterns through effects on PTEN function in the nucleus, adding a layer by which PRMT6 connects methylation of a tumor suppressor to modulation of both survival signaling and RNA processing. |
