PRMT5 activity sustains histone production to maintain genome integrity

ABSTRACT: Histone proteins package DNA into nucleosomes, forming chromatin and thereby safeguarding genome in-tegrity. Proper histone expression is essential for cell proliferation and chromatin organization, yet the up-stream regulators of histone supply remain incompletely understood. PRMT5—a cell essential type II protein arginine methyltransferase frequently overexpressed in cancer—catalyzes symmetric dimethylation of argi-nine residues. Using time-resolved nascent transcriptional profiling, quantitative proteomics, and high-resolution imaging, we show that PRMT5 activity is required to sustain histone transcription and histone pro-tein synthesis during S phase. PRMT5 inhibition or knockdown leads to rapid histone mRNA depletion, loss of histone proteins, and accumulation of replication-associated 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. In this experiment, we tested if PRMT5 inhibition induced histone H3K4me3 changes or H3K27me3 heterochromatin spreading.

ORGANISM(S): Homo sapiens

PROVIDER: GSE301721 | GEO | 2026/09/01

REPOSITORIES: GEO