PRMT5 activity sustains histone production to maintain genome integrity

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.