Biology subjects

Azofeifa, J.

Publications and source records attributed to Azofeifa, J..

2 recordsLinked to original sources

bioRxiv2025

PRMT5 activity sustains histone production to maintain genome integrity

Histone proteins package DNA into nucleosomes, forming chromatin and thereby safeguarding genome integrity. Proper histone expression is essential for cell proliferation and chromatin organization, yet the upstream regulators of histone supply remain incompletely understood. PRMT5--a cell essential type II protein arginine methyltransferase frequently overexpressed in cancer--catalyzes symmetric dimethylation of arginine residues. Using time-resolved nascent transcriptional profiling, quantitative proteomics, and imaging, we show that PRMT5 activity is required to sustain histone transcription and histone protein synthesis during S phase. PRMT5 inhibition or knockdown leads to rapid histone mRNA depletion, loss of histone proteins, and accumulation of replicationassociated nuclear abnormalities. We further show that soluble histone H4 accumulates at histone locus bodies (HLBs) upon PRMT5 inhibition, and that PRMT5-substrate H4 Arginine 3 mutants localize more robustly to HLBs than do wildtype H4. These findings support a model in which PRMT5-mediated methylation of histone H4 regulates histone transcription. Our findings establish PRMT5 as a central coordinator of histone homeostasis and provide a mechanistic rationale for its essential role in proliferating cells.

cell biology↗

bioRxiv2024

Productive mRNA Chromatin Escape is Promoted by PRMT5 Methylation of SNRPB

Protein Arginine Methyltransferase 5 (PRMT5) regulates RNA splicing and transcription by symmetric dimethylation of arginine residues (Rme2s/SDMA) in many RNA binding proteins. However, the mechanism by which PRMT5 couples splicing to transcriptional output is unknown. Here, we demonstrate that a major function of PRMT5 activity is to promote chromatin escape of a novel, large class of mRNAs that we term Genomically Retained Incompletely Processed Polyadenylated Transcripts (GRIPPs). Using nascent and total transcriptomics, spike-in controlled fractionated cell transcriptomics, and total and fractionated cell proteomics, we show that PRMT5 inhibition and knockdown of the PRMT5 SNRP (Sm protein) adapter protein pICln (CLNS1A) --but not type I PRMT inhibition--leads to gross detention of mRNA, SNRPB, and SNRPD3 proteins on chromatin. Compared to most transcripts, these chromatin-trapped polyadenylated RNA transcripts have more introns, are spliced slower, and are enriched in detained introns. Using a combination of PRMT5 inhibition and inducible isogenic wildtype and arginine-mutant SNRPB, we show that arginine methylation of these snRNPs is critical for mediating their homeostatic chromatin and RNA interactions. Overall, we conclude that a major role for PRMT5 is in controlling transcript processing and splicing completion to promote chromatin escape and subsequent nuclear export.

molecular biology↗