Histone modifications ubiquitination

Regulating mono-ubiquitination of proteins by DUBs is important in histone modification where ubiquitination is thought to modulate chromatin structure and transcriptional activity. Normally, about 10% of the histone core octomers contain ubiquitinated histones and the ubiquitin is removed at mitosis by DUB activity. UBP8 has been demonstrated to regulate the ubiquitination of histone H2B, which is important in transcriptional activation of many genes [88]. 

Fig. 1. Core histone modifications. Human histone N-terminal and in some cases C-terminal amino acid sequences are shown. The modifications include methylation (M), acetylation (Ac), phosphorylation (P), ubiquitination (U), and ADP ribosylation (step ladder). The sites of trypsin digestion of histones in nucleosomes are indicated (T).

Analyses of the reeonstituted eomplexes by quantitative agarose gel electrophoresis [404,405] and analytical ultracentrifugation [266,406] in the presence of MgCl2 showed that the arrays were able to fold in a way that is almost indistinguishable from complexes reconstituted with major histones (see Fig. 14A-B). Despite this, it was found that histone H2A ubiquitination affects the MgCl2 solubility of the reconstituted complexes (see Fig. 14C) suggesting that this modification may play a role in enhancing the intermolecular associations between chromatin fibers [221]. 

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].)...

Figure 1 Histone modifications. The best-characterized human histone modifications are shown which include the acetylation of lysines (Ac), the methylation of lysines and arginines (Me)/ the phosphorylation of serine and threonines (Ph), and the ubiquitination of lysines (Ub). The vast majority of modifications are within the N-terminal domain of the histone tail/ but ubiquitination occurs at the C-terminal domain.

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

Shi Y, Lan L, Matson C, Mulhgan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSDl. Cell 119 941-953 Shilatifard A (2006) Chromatin Modifications by Methylation and Ubiquitination Implications in the Regulation of Gene Expression. Annu Rev Biochem 75 243-269 Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol. Mol Biol Rev 64 435-459... 

The covalent modifications of histone tails such as acetylation, phosphorylation, and ubiquitination have been shown to be reversible. This reversibility help the cells to respond to these regulatory modifications and thereby, influence the gene expression. Methylation of histones however, has been considered to be a relatively stable and irreversible mark on histones. Nevertheless active turnover of methyl groups on histones do exist. One of the possible mechanism of removal of methyl... 

Another speculation has been put forth. Because the turnover of methyl groups such as the modification on lysine residues is low, ubiquitination of histone N-termini might serve as a signal for proteolysis of methylated histones such that dynamic regulation of the chromatin is possible. Since no histone demethylases have been identified, ubiquitin-mediated proteolysis might be a way to reverse the effects of histone methylation. ... 

The four core histones, H2A, H2B, H3, H4 and their variants, and the linker histone HI subtypes are susceptible to a wide range of post-synthetic modifications, including acetylation, phosphorylation, methylation, ubiquitination, and ADP-ribosylation (Figs. 1 and 2). In this chapter, the four latter modifications and their functions in chromatin structure and function are presented. 

Fig. 11. Trans-histone regulatory pathway. Modification of yeast histone H3 at Lys-4 and Lys-79 is dependent upon ubiquitination of histone H2B at Lys-123.

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.

Histones within transcriptionally active chromatin and heterochromatin also differ in their patterns of covalent modification. The core histones of nucleosome particles (H2A, H2B, H3, H4 see Fig. 24-27) are modified by irreversible methylation of Lys residues, phosphorylation of Ser or Thr residues, acetylation (see below), or attachment of ubiquitin (see Fig. 27-41). Each of the core histones has two distinct structural domains. A central domain is involved in histone-histone interaction and the wrapping of DNA around the nucleosome. A second, lysine-rich amino-terminal domain is generally positioned near the exterior of the assembled nucleosome particle the covalent modifications occur at specific residues concentrated in this amino-terminal domain. The patterns of modification have led some researchers to propose the existence of a histone code, in which modification patterns are recognized by enzymes that alter the structure of chromatin. Modifications associated with transcriptional activation would be recognized by enzymes that make the chromatin more accessible to the transcription machinery. 

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