N-formylation of lysine in histone proteins as a secondary modification arising from oxidative DNA damage

Abstract

The posttranslational modification of histone and other chromatin proteins has a well recognized but poorly defined role in the physiology of gene expression. With implications for interfering with these epigenetic mechanisms, we now report the existence of a relatively abundant secondary modification of chromatin proteins, the N 6 -formylation of lysine that appears to be uniquely associated with histone and other nuclear proteins. Using both radiolabeling and sensitive bioanalytical methods, we demonstrate that the formyl moiety of 3 -formylphosphate residues arising from 5 -oxidation of deoxyribose in DNA, caused by the enediyne neocarzinostatin, for example, acylate the N 6 -amino groups of lysine side chains. A liquid chromatography (LC)-tandem mass spectrometry (MS) method was developed to quantify the resulting N 6 -formyl-lysine residues, which were observed to be present histone acetylation ͉ oxidative stress ͉ enediyne

Molecular Basis of Maillard Amide-Advanced Glycation End Product (AGE) Formation in Vivo

“…The idea to explain the 2-fold increase of formyl lysine in uremia based on the in vitro models is undermined by the fact that neither 1-DG nor glucosone have been detected in vivo so far. An intriguing alternative mechanism might be the with inflammation increased oxidative DNA breakdown to give 3Ј-formylphosphate-ended DNA fragments as a potential precursor, but again, such species have not been identified in vivo (23).…”

“…In addition, it could be identified in incubation mixtures of various sugars, l-ascorbic acid or l-dehydroascorbic acid with poly-l-lysine and ␤-lactoglobulin, respectively (22). Jiang et al (23) observed transfer of formyl groups from 3Ј-formylphosphate-ended DNA, arising from oxidation of the 5Ј-position of deoxyribose and subsequent DNA strand breakage by the enediyne antibiotic neocarzinostatin, to histone proteins in human TK6 cells to give N 6 -formyl lysine.…”

Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH

“…Protein acetylation has furthermore been recognized as a general posttranslational modification with biological implications in numerous pathways, especially in metabolism (6 -11). In addition to lysine acetylation, examples of formylation (12), propionylation and butyrylation (13)(14)(15), and myristoylation (16 -18) have been reported. More recently, the list of acyl groups has been extended considerably with malonyl (19,20), succinyl (19 -21), glutaryl (22), crotonyl (23,24), ␣-hydroxyisobutyryl (25), and 3-phosphoglyceryl (26), thus extending the scope of acyl-based posttranslational modifications considerably (10,(27)(28)(29)(30).…”

Initial characterization of histone H3 serine 10 O-acetylation

“…9 Among others, new sites of acetylation, methylation, O-GlcNAcylation, crotonylation, propionylation, arginine citrullination, butyrylation, proline isomerization, malonylation, succinylation, formylation, and ADP-ribosylation have been detected and studied in a wide range of species and biological processes. [10][11][12][13][14][15][16] Serine acetylation was first reported as a chemical antagonist to phosphorylationmediated signaling pathways in eukaryotic cells, catalyzed by the Yersinia bacterial virulence factor, YopJ. 17 YopJ specifically acetylates a serine residue that is otherwise an acceptor site for shown) but, more significantly, novel categories of histone PTMs such as serine and threonine O-acetylation on histone H3.…”