GLYCATION AND GLYCOXIDATION OF HISTONES BY ADP-RIBOSE

The reaction of long lived proteins with reducing sugars has been impl icated in the pathophysiology of aging and age-related diseases, A lik ely intranuclear source of reducing sugar is ADP-ribose, which is gene rated following DNA damage from the turnover of ADP-ribose polymers, I n this study, ADP-ribose has been shown to be a potent histone glycati on and glycoxidation agent in vitro. Incubation of ADP ribose with his tones H1, H2A, H2B, and H4 at pH 7.5 resulted in the formation of keto amine glycation conjugates, Incubation of histone H1 with ADP-ribose a lso rapidly resulted in the formation of protein carboxymethyllysine r esidues, protein-protein cross-links, and highly fluorescent products with properties similar to the advanced glycosylation end product pent osidine. The formation of glycoxidation products was related to the de gradation of ketoamine glycation conjugates by two different pathways, One pathway resulted in the formation of protein carboxymethyllysine residues and release of an ADP moiety containing a glyceric acid fragm ent, A second pathway resulted in the release of ADP, and it is postul ated that this pathway is involved in the formation of histone-histone cross-links and fluorescent advanced glycosylation end products.