Histone Deacetylase 1 Inhibition by Peptides Containing a DNA Damage-Induced, Nonenzymatic, Histone Covalent Modification.

Treatment of HeLa cells with the DNA damaging agent, bleomycin (BLM), results in the formation of a nonenzymatic 5-methylene-2-pyrrolone histone covalent modification on lysine residues (K MP ). K MP is much more electrophilic than other N -acyllysine covalent modifications and post-translational modifications, including N -acetyllysine (K Ac ). Using histone peptides containing K MP , we show that this modification inhibits the class I histone deacetylase, HDAC1, by reacting with a conserved cysteine (C261) located near the active site. HDAC1 is inhibited by histone peptides whose corresponding N -acetylated sequences are known deacetylation substrates, but not one containing a scrambled sequence. The HDAC1 inhibitor, trichostatin A, competes with covalent modification by the K MP -containing peptides. HDAC1 is also covalently modified by a K MP -containing peptide in a complex milieu. These data indicate that peptides containing K MP are recognized by HDAC1 and are bound in the active site. The effects on HDAC1 indicate that K MP formation in cells may contribute to the biological effects of DNA damaging agents, such as BLM, that form this nonenzymatic covalent modification.