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 protein arginine methyltransferase that catalyzes symmetric dimethylation of arginine residues, is frequently overexpressed in cancer and targeted in multiple clinical trials, but its cell-essential function remains unclear. 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, p53-independent depletion of histone mRNA, leading to loss of histone proteins and accumulation of replication-associated nuclear abnormalities. Parallel depletion of the histone gene transcription factor HINFP produces similar genomic instability, linking defective histone production to loss of genome integrity. We further show that histone H4 accumulates at both histone genes and histone locus bodies (HLBs) and that H4R3me2s is enriched at HLBs. 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.