Protein arginine methylation promotes global 3'UTR shortening in proliferating cells.

Protein arginine methyltransferases (PRMTs) are promising anti-cancer targets, but their tumorigenic mechanisms remain incompletely understood. Here, we show that arginine methylation drives global 3'UTR shortening, thereby promoting oncogenic short isoforms. Inhibition of asymmetric dimethylation reverses this shift, with combined inhibition of asymmetric and symmetric dimethylation (DMAi) producing an even greater effect across human cancer cell lines, patient-derived organoids, and activated murine T cells, while also counteracting the shortening induced by reduced CFIm25 expression. Arginine methylation promotes PCF11 association with the cleavage and polyadenylation machinery, enabling efficient processing of weak proximal poly(A) sites within transcripts characterized by high GC content, large distances between alternative poly(A) sites, and a position-dependent sequence code. These findings establish physiologic roles of PRMTs in promoting 3'UTR shortening, which could be exploited for patient stratification of PRMT-targeting therapies in oncology and immune-related diseases.