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Effects of Carcinogens and Other Agents on Histone Methylation by a Histone Arginine Methyltransferase Purified from Rat Liver Cytoplasm

Department of Pathology, College of Medicine, University of Florida, Gainesville, Florida 32611

S-Adenosyl-L-ethionine has been found to inhibit histone methylation by an arginine methyltransferase purified from rat liver cytoplasm, in the presence of S-adenosyl-L-methionine. The enzyme is able to transfer alkyl groups from either of the activated amino acids to histone and with comparable efficiency. Histone methylation is also inhibited by N-hydroxy-2-acetylaminofluorene (40% at 1 mM inhibitor concentration) and N-acetoxy-2-acetylaminofluorene (69% at 1.0 mM inhibitor concentration). The arginine methyltransferase has a K_m value of 4.4 µM and is subject to product inhibition by S-adenosyl-L-homocysteine (K_i = 1.2 µM). Other similarities to the transfer ribonucleic acid methyltransferases are susceptibility to inhibition by adenine and the adenosine analogs, tubercidin and N-6-(²-isopentenyl) adenosine (16, 79, and 72%, respectively, at 1.0 mM inhibitor concentrations). The dyes ethidium bromide and acridine orange also inhibit the methyltransferase system (58 and 80%, respectively, at 1.0 mM inhibitor concentrations). The observation that arginine methylation in histones is inhibited by reactive metabolites of carcinogenic agents is used as a basis for proposing that interference in the normal histone methylation process, with resultant effects on fidelity of gene expression represents a preliminary step in carcinogenesis by such agents.

¹ Supported in part by NIH Grants CA13408 and GM19074.

Received 9/14/73. Accepted 3/ 5/74.