biostudies-literatureJacinto MPNational Institute of General Medical SciencesNIGMS NIH HHS1388-1393https://www.ebi.ac.uk/biostudies/studies/S-EPMC10124317biostudies-literatureUnknown62(8)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 <i>N</i>-acyllysine covalent modifications and post-translational modifications, including <i>N</i>-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 <i>N</i>-acetylated sequences are known deacetylation substrates, but not one containing a scrambled sequence. The HDAC1 inhibitor, trichostatin A, BiochemistryHistone Deacetylase 1 Inhibition by Peptides Containing a DNA Damage-Induced, Nonenzymatic, Histone Covalent Modification.PMC10124317GM-131736R35 GM131736Jacinto MPGreenberg MMfalseHistone 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 <i>N</i>-acyllysine covalent modifications and post-translational modifications, including <i>N</i>-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 <i>N</i>-acetylated sequences are known deacetylation substrates, but not one containing a scrambled sequence. The HDAC1 inhibitor, trichostatin A, 2023-01-01T00:00:00Z2023 Apr2026-04-29T14:14:15.613Z2025-04-06T00:49:35.649ZS-EPMC101243173697222310.1021/acs.biochem.3c00007