Productive mRNA chromatin escape is promoted by PRMT5 activity

Abstract

Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric arginine dimethylation (Rme2s) of RNA-binding proteins and influences RNA splicing and gene expression. However, how PRMT5 couples splicing to productive transcript output remains unclear. We show that a major function of PRMT5 is to promote chromatin escape of mRNAs, designated as genomically retained incompletely processed polyadenylated transcripts (GRIPPs). Using nascent and spike-in normalized fractionated transcriptomics with proteomics, we find that PRMT5 inhibition in mammalian cells causes polyadenylated mRNA and Smith antigen (Sm) protein accumulation on chromatin. These retained transcripts are intron rich and splice slowly. PRMT5 inhibition and isogenic SNRPB mutants demonstrate that Sm tail methylation is essential to prevent RNA detention on chromatin. Biochemical assays reveal that the SMN Tudor domain competes with nucleic acid binding of methylated Sm tails. We conclude that PRMT5 ensures mRNA processing and nuclear export by preventing aberrant chromatin retention, highlighting arginine methylation as a key regulator of RNA-chromatin dynamics.

Keywords: CLNS1A; PRMT5; RIOK1; Rme2s; SDMA; SMN; SNRPB; SNRPD1; SNRPD3; pICln.