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N-Formylation of Lysine in Histone Proteins as a Secondary Modification Arising from Oxidative DNA Damage
Tao Jiang, Xinfeng Zhou, Koli Taghizadeh, Min Dong and Peter C. Dedon
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 1 (Jan. 2, 2007), pp. 60-65
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25426050
Page Count: 6
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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 N⁶-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 N⁶-amino groups of lysine side chains. A liquid chromatography (LC)-tandem mass spectrometry (MS) method was developed to quantify the resulting N⁶-formyl-lysine residues, which were observed to be present in unperturbed cells and all sources of histone proteins to the extent of 0.04-0.1% of all lysines in acid-soluble chromatin proteins including histones. Cells treated with neocarzinostatin showed a clear dose-response relationship for the formation of N⁶-formyl-lysine, with this nucleosome linker-selective DNA-cleaving agent causing selective N⁶-formylation of the linker histone H1. The N⁶-formyl-lysine residue appears to represent an endogenous histone secondary modification, one that bears chemical similarity to lysine N⁶-acetylation recognized as an important determinant of gene expression in mammalian cells. The N⁶-formyl modification of lysine may interfere with the signaling functions of lysine acetylation and methylation and thus contribute to the pathophysiology of oxidative and nitrosative stress.
Proceedings of the National Academy of Sciences of the United States of America © 2007 National Academy of Sciences