HEMK2 is a multifunctional methyltransferase that catalyzes post-translational modifications on diverse substrates. As the catalytic subunit of a heterodimer with TRMT112, HEMK2 monomethylates histone H4 lysine 12 (H4K12me1), a modification enriched at promoters of cell cycle regulator genes 1. HEMK2 also catalyzes N5-methylation of glutamine residues within the conserved GGQ motif of eukaryotic release factor 1 (eRF1) and other proteins containing a Gly-Gln-X3-Arg sequence context 23. ETF1 methylation requires its complexation with ERF3 in the GTP-bound state 4. Recent structural studies reveal HEMK2 utilizes distinct substrate-binding pockets to accommodate both lysine and glutamine residues, though it exhibits stronger preference for glutamine methylation 5. Beyond protein modification, HEMK2 participates in arsenic metabolism by converting monomethylarsonous acid to less toxic dimethylarsonic acid, though this represents a limited role compared to AS3MT 6. Clinically, HEMK2 depletion impairs proliferation of androgen-dependent and castration-resistant prostate cancer cells, linking H4K12 methylation to cancer cell growth regulation 1. TRMT112 regulates HEMK2 expression through quality control mechanisms, ensuring only functional isoforms persist in cells 7.