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N-Formylation of Lysine in Histone Proteins As a Secondary Modification Arising from Oxidative DNA Damage

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N-Formylation of Lysine in Histone Proteins As a Secondary Modification Arising from Oxidative DNA Damage 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§ Biological Engineering Division and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 Edited by Jacqueline K. Barton, California Institute of Technology, Pasadena, CA, and approved October 31, 2006 (received for review August 7, 2006) The posttranslational modification of histone and other chromatin of nucleophilic amino acids that make them likely targets for proteins has a well recognized but poorly defined role in the pathological secondary modification. The primary level of or- physiology of gene expression. With implications for interfering ganization of eukaryotic nuclear DNA involves packaging of with these epigenetic mechanisms, we now report the existence of DNA as nucleosomes, each consisting of a core containing Ϸ145 a relatively abundant secondary modification of chromatin pro- bp of DNA wrapped around an octamer of histone proteins teins, the N6-formylation of lysine that appears to be uniquely H2A, H2B, H3, and H4, with adjacent cores linked by 30–50 bp associated with histone and other nuclear proteins. Using both of DNA and a fifth or linker histone, H1 (8, 9). In general terms, radiolabeling and sensitive bioanalytical methods, we demon- each histone protein is comprised of a globular central domain strate that the formyl moiety of 3؅-formylphosphate residues with lysine- and arginine-rich C and N termini that make arising from 5؅-oxidation of deoxyribose in DNA, caused by the extensive contact with the nucleosomal DNA (8, 9) and are the enediyne neocarzinostatin, for example, acylate the N6-amino major sites for posttranslational modification by methylation, groups of lysine side chains. A liquid chromatography (LC)–tandem acetylation, and phosphorylation of amino acid side chains. mass spectrometry (MS) method was developed to quantify the These modifications are now widely recognized as a major resulting N6-formyl-lysine residues, which were observed to be epigenetic mechanism for controlling gene expression (10), and present in unperturbed cells and all sources of histone proteins to there is an emerging appreciation for the relationship between the extent of 0.04–0.1% of all lysines in acid-soluble chromatin aberrant modifications and carcinogenesis (1, 11). Although the proteins including histones. Cells treated with neocarzinostatin secondary modification of histones by acetylation of lysine showed a clear dose–response relationship for the formation of N6-amino groups (Fig. 1) has been known for 40 years (12, 13), N6-formyl-lysine, with this nucleosome linker-selective DNA-cleav- it has only recently been identified as a critical determinant of ing agent causing selective N6-formylation of the linker histone H1. gene expression (14) and a general modulator of p53 and other The N6-formyl-lysine residue appears to represent an endogenous transcription factors (15, 16). Unlike the N-terminal ␣-acetyla- histone secondary modification, one that bears chemical similarity tion of proteins that occurs with translation, lysine N6- to lysine N6-acetylation recognized as an important determinant of acetylation is reversible and occurs at highly conserved sites in gene expression in mammalian cells. The N6-formyl modification of the N-terminal tails of histone proteins (14). Acetylation is lysine may interfere with the signaling functions of lysine acety- thought to affect gene expression by disrupting electrostatic lation and methylation and thus contribute to the pathophysiology histone–DNA interactions and by serving as a recognition of oxidative and nitrosative stress. element for bromodomain modules of various chromatin remod- eling proteins and transcription factors (17). By whatever mech- histone acetylation ͉ oxidative stress ͉ enediyne anism, lysine acetylation is controlled by two classes of enzymes (Fig. 1): histone acetyltransferases and histone deacetylases (14, here is a growing appreciation for the complex relationship 18). Human cells contain several members of each class of Tbetween posttranslational modification of histone and other protein, with both cytosolic and nuclear forms (14). chromatin proteins and regulation of most DNA-based pro- As shown in Fig. 2, oxidation of deoxyribose produces a variety cesses, including DNA replication, transcription, repair and of electrophilic products that have the potential to react with recombination, and chromosome segregation (1–4). Among the nucleophilic sites in cellular DNA, RNA, and proteins. For modifications affecting the N and C termini of histone proteins example, the base propenal product of 4Ј-oxidation of deoxyri- are lysine acetylation, lysine and arginine methylation, serine bose in DNA has been shown to be a major cellular source of the phosphorylation, ubiquitination, and ADP ribosylation (1–4). mutagenic endogenous DNA adduct, M1G (19). The present Inasmuch as these modifications represent electrophilic adducts work addresses protein adducts formed by the 3Ј-formylphos- of nucleophilic side chains of amino acids, it is reasonable to assume that lysine-rich histone proteins would be subject to chemical reactions with electrophilic oxidation products of lipids Author contributions: T.J., M.D., and P.C.D. designed research; T.J., X.Z., M.D., and K.T. and other biomolecules. For example, electrophilic products of performed research; T.J., X.Z., and K.T. contributed new reagents/analytic tools; T.J., X.Z., lipid peroxidation, such as malondialdehyde and the ␣,␤- K.T., and P.C.D. analyzed data; and T.J. and P.C.D. wrote the paper. unsaturated hydroxyalkenals, have been detected as protein The authors declare no conflict of interest. adducts under conditions of oxidative stress (5–7). We now This article is a PNAS direct submission. report that histone proteins are subject to a noncanonical Abbreviations: LC, liquid chromatography; MS/MS, tandem MS; PITC, phenylisothiocyanate. secondary modification that arises from oxidative DNA damage: *Present address: Department of Biochemistry, Tufts University School of Medicine, 150 N-formylation of the side-chain amino group of lysine (Fig. 1) by Harrison Avenue, Boston, MA 02111. transacylation with the highly reactive 3Ј-formylphosphate res- †Present address: Barclays Global Investors, 45 Freemont Street, San Francisco, CA 94105. idues arising from 5Ј-oxidation of deoxyribose in DNA. This ‡Present address: Novartis Pharma AG, Basel CH-4002, Switzerland. endogenous mimic of lysine N6-acetylation has the potential to §To whom correspondence should be addressed. E-mail: [email protected]. interfere with the physiology of normal histone modifications. This article contains supporting information online at www.pnas.org/cgi/content/full/ Among the proteins capable of reacting with endogenously 0606775103/DC1. generated electrophiles, histone proteins contain an abundance © 2006 by The National Academy of Sciences of the USA 60–65 ͉ PNAS ͉ January 2, 2007 ͉ vol. 104 ͉ no. 1 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0606775103 Downloaded by guest on September 29, 2021 Fig. 1. N6-formyl-lysine residues arising from products of oxidative DNA damage are chemical analogs of the biologically important lysine N6- acetylation. phate residue that arises from oxidation of the 5Ј-position of deoxyribose along with a 5Ј-(2-phosphoryl-1,4-dioxobutane) species (Fig. 2). The labile phosphate ester of the formylphos- phate promotes transfer of the formyl group to primary and Fig. 3. HPLC analysis of neocarzinostatin-induced 3H-labeling of histones Ј 3 secondary amines (20). That the 5Ј-position of deoxyribose in from TK6 cells with DNA containing 5 -[ H]thymidine (Upper) or methyl- [3H]thymidine (Lower). Isolated nuclei were treated with neocarzinostatin (30 DNA is the most solvent accessible site in the B-helix suggests ␮ Ј Ј M; shaded bars) or methanol vehicle (open bars), followed by histone that 3 -formylphosphate residues and other 5 -oxidation prod- extraction, nuclease digestion, and HPLC separation, as described in Materials ucts will be among the most common features of DNA strand and Methods. Tritium associated with the various histone-containing HPLC breaks in cells (21). fractions was quantified by scintillation counting and reported as disintegra- Given the proximity of lysine-rich histone proteins to DNA in tions per minute (DPM) per unit area of UV absorbance signal. Data represent nuclei, one might expect that oxidative DNA damage would mean Ϯ SD for three independent experiments. result in the reaction of deoxyribose oxidation products with histone proteins to cause noncanonical protein secondary mod- ifications. Here we present evidence for just such a mechanism the radiolabel in histone proteins by scintillation counting. To Ј 3 with N6-formylation of lysines in histone proteins by reaction this end, DNA in human TK6 cells was labeled with [5 - H2]- or 3 with the 3Ј-formylphosphate residues of deoxyribose oxidation [methyl- H]thymidine by addition of the deoxynucleoside to the in DNA. Further, we observed significant lysine N6-formylation culture medium, which resulted in incorporation of one radio- only in histone proteins, which raises the possibility of an labeled thymidine for every 10–30 unlabeled thymidines (data endogenous secondary modification with the potential for in- not shown). Isolated nuclei were then treated with neocarzinos- terference with N6-acetylation of lysine. tatin,
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