Intracellular Formation of a DNA Damage-Induced, Histone Post-Translational Modification Following Bleomycin Treatment

Evaluating the significance of various forms of DNA damage is complicated by discoveries that some lesions inactivate repair enzymes or produce more deleterious forms of damage. Histone lysines within nucleosomes react with the commonly produced C4'-oxidized abasic site (C4-AP) to concomitantly yield an electrophilic modification (K-MP) on lysine and DNA strand scission. We developed a chemoproteomic approach to identify K-MP in HeLa cells. More than 60 000 K-MP-modified histones are produced per cell. Using LC-MS/MS, we detected K-MP at 17 of the 57 lysine residues distributed throughout the four core histone proteins. Therefore, K-MP constitutes a DNA damage-induced, nonenzymatic histone post-translational modification. K-MP formation suggests that downstream processes resulting from DNA damage could have ramifications on cells.