This feedback loop explains why PRMT5 is cell-essential: by coordinating histone supply, PRMT5 ensures proper chromatin assembly, genome integrity & cell proliferation. No PRMT5 = no histones = stalled growth. @JacobRoth13.

Check it out: doi.org/10.1101/2025.07.03.663002

5/5

Mechanistically, soluble histone H4 accumulates at histone locus bodies upon PRMT5 inhibition, and H4 R3 mutants localize more robustly than WT—supporting methylation-driven feedback at histone loci.
4/5

Inhibiting or knocking down PRMT5 triggers rapid histone mRNA depletion, histone protein loss & replication-associated nuclear abnormalities (micronuclei, γH2AX foci), directly linking arginine methylation to genome stability.
3/5

Using time-resolved nascent transcription profiling, quantitative proteomics & imaging, we show that PRMT5 is required to sustain histone mRNA transcription & histone protein synthesis during S-phase—when demand for new histones peaks.
2/5

That foundation of basic science, funded by the NIH and DoD/CDMRP, led us here: to a druggable AML vulnerability.
Basic science matters. So does federal funding. /end

This story began with our curiosity-driven work in Xenopus frogs and proteins—studying glutamate-glutamylation in basic chromatin biology of histone chaperone function. bit.ly/4j7uEnB and and go.nature.com/42GgDXW and bit.ly/3XVCrMJ /7

TTLL4 is a post-translational regulator of leukemia maintenance.
It’s druggable. It’s specific. And it’s a promising new angle in a challenging AML subtype.
This is exactly the kind of science made possible by federal funding. /6