Quantitative Analysis of Histone Modifications: Formaldehyde Is a Source of Pathological N-Formyllysine That Is Refractory to Histone Deacetylases

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Aberrant protein modifications play an important role in the pathophysiology of many human diseases, in terms of both dysfunction of physiological modifications and the formation of pathological modifications by reaction of proteins with endogenous electrophiles. Recent studies have identified a chemical homolog of lysine acetylation, N⁶-formyllysine, as an abundant modification of histone and chromatin proteins, one possible source of which is the reaction of lysine with 3′-formylphosphate residues from DNA oxidation. Using a new liquid chromatography-coupled to tandem mass spectrometry method to quantify all N⁶-methyl-, -acetyl -⁠ and -formyl-lysine modifications, we now report that endogenous formaldehyde is a major source of N⁶-formyllysine and that this adduct is widespread among cellular proteins in all compartments. N⁶-formyllysine was evenly distributed among different classes of histone proteins from human TK6 cells at 1–4 modifications per 10⁴ lysines, which contrasted strongly with lysine acetylation and mono-, di-, and tri-methylation levels of 1.5-380, 5-870, 0-1400, and 0-390 per 10⁴ lysines, respectively. While isotope labeling studies revealed that lysine demethylation is not a source of N⁶-formyllysine in histones, formaldehyde exposure was observed to cause a dose-dependent increase in N⁶-formyllysine, with use of [¹³C,²H₂]-formaldehyde revealing unchanged levels of adducts derived from endogenous sources. Inhibitors of class I and class II histone deacetylases did not affect the levels of N⁶-formyllysine in TK6 cells, and the class III histone deacetylase, SIRT1, had minimal activity (<10%) with a peptide substrate containing the formyl adduct. These data suggest that N⁶-formyllysine is refractory to removal by histone deacetylases, which supports the idea that this abundant protein modification could interfere with normal regulation of gene expression if it arises at conserved sites of physiological protein secondary modification.

Vyšlo v časopise: Quantitative Analysis of Histone Modifications: Formaldehyde Is a Source of Pathological N-Formyllysine That Is Refractory to Histone Deacetylases. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003328
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003328

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