Post-translational modifications histone phosphorylation

As described above, histones are much more than passive structural players within chromatin. Dynamic post-translational modifications of these proteins confer specialized chemical proprieties to chromatin of both informational and structural nature with important functional implications. The highly conserved sites for acetylation, methylation, phosphorylation, ADP-ribosylation, and ubiquitination events on histone tails appear to orchestrate functional activities that range from transcriptional activation and repression to DNA repair and recombination. 

Fig. 6. Post-translational modifications of core and linker histones. The sites of acetylation, phosphorylation, poly-ADP ribosylation, methylation, and ubiquitination are incficated by numbers that correspond to the amino acid position from the N-termini of the molecules. The nomenclature of histone HI variants is as in Fig. 3. The length of C- and N-terminal tails is in relative scale between core histones to illustrate primary structural differences between these proteins.

A true appreciation of the subtle and complex ways in which the nucleosome can influence gene expression, has come only recently, largely through studies of the post-translational modifications to which all histones are subject and of the enzymes that add and remove these modifications. It has been known for many years that the histone N-terminal tails are exposed on the surface of the nucleosome and that selected amino acid residues are subject to a variety of enzyme-catalyzed, post-translational modifications. These include acetylation of lysines, phosphorylation of serines, and methylation of lysines and arginines ([6,7], see also chapters by Davie, and Ausio and Abbott, this volume). The locations of the histone N-terminal tails in the nucleosome and the residues that can be modified are shown in Fig. 1. 

Fig. 1. Histone modifications on the nucleosome core particle. The nucleosome core particle showing 6 of the 8 core histone N-terminal tail domains and 2 C-terminal tails. Sites of post-translational modification are indicated by coloured symbols that are defined in the key (lower left) acK = acetyl lysine, meR = methyl arginine, mcK = methyl lysine, PS = phosphoryl serine, and uK = ubiquitinated lysine. Residue numbers are shown for each modification. Note that H3 lysine 9 can be either acetylated or methylated. The C-terminal tail domains of one H2A molecule and one H2B molecule are shown (dashed lines) with sites of ubiquitination at H2A lysine 119 (most common in mammals) and H2B lysine 123 (most common in yeast). Modifications are shown on only one of the two copies of histones H3 and H4 and only one tail is shown for H2A and H2B. Sites marked by green arrows are susceptible to cutting by trypsin in intact nucleosomes. Note that the cartoon is a compendium of data from various organisms, some of which may lack particular modifications e.g., there is no H3meK9 in S. cerevisiae. (From Ref [7].)...

In cells of the mammary gland, either in normal epithelial or in cancerous cells, the packaging of chromosomal DNA into chromatin restricts the access of the transcription machinery, thereby causing transcriptional repression. The basic N-termini of histones are subject to post-translational modifications, including lysine acetylation, lysine and arginine methylation, serine phosphorylation and ubiquitinylation [56]. It has been proposed in the histone code hypothesis that the intricate pattern of modifications of the N-terminal histone tail influences gene regulation [57]. 

Histones are basic proteins that are made up by a globular domain and an N-terminal tail that protrudes from the nucleosome. Nucleosomes form the basic unit of chromatin and are made up by a complex of DNA wrapped around an octamer of histones formed by pairs of the histones H2A, H2B, H3, and H4 (45,46) (Fig. 1). Post-translational modification of the core histone tails by methylation, acetylation, phosphorylation, ubiquitina-tion, or sumoylation can alter the structure of the nucleosomes and thus alter gene expression. These post-translational modifications determine the structure and pattern of chromatin condensation and determine the histone code that drives gene transcriptional regulation (47,48). Below are briefly described the factors determining the histone acetylation and methylation. 

Histones are core proteins which form nucleosomes with DNA, in which an octamer of two copies of each of four different histones H2A, H2B, H3, and H4 are wrapped by DNA. This nucleosome is a basic unit of chromatin. Post-translational modifications of histones, such as acetylation, methylation, and phosphorylation, play an important role in gene regulation [90]. Although the synthesis of histones H2B [91] and H4 [92, 93], which contain no Cys residues, has been reported based on the combination of NCL and a desulfurization strategy by several groups, the synthesis of the Cys residue-containing histone H3 is difficult and has enjoyed limited success [72, 92, 94]. Recently, one-pot synthesis of H3 using peptide hydrazide as a peptide thioester precursor was reported [95]. 

Figure 5.3 Selected post-translational modifications of human histones. Methylation, acetylation, phosphorylation, biotinylation and ubiquitylation sites have been identified on all four core histones. The modifications shown here should not be regarded as a complete or final list.

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