Histone tails phosphorylation

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. 

Histone phosphorylation is a common posttranslational modification fond in histones, primarily on the N-terminal tails. Phosphorylation sites include serine and threonine residues, tyrosine phosphorylation has not been observed so far. Some phosphorylation events occur locally whereas others occur globally throughout all chromosomes during specific events like mitosis. Histone phosphorylation is catalyzed by kinases. Removal of the phosphoryl groups is catalyzed by phosphatases. 

Histone tails are the N-terminal regions of histones which reach outside the nucleosomes. They are not essential for the formation in of nucleosomes but are required for the formation of higher-order chromatin structures. The histone tails are also known to be heavily posttranslationally modified by acetylation, phosphorylation, methylation, etc. and are important for the regulation of gene activity. 

Histone Acetylation Histone Deacetylases Histone Methylation Histone Phosphorylation Histone Tails Hrv... 

Figure 1. Hierarchical model of chromosome structure, (a) In interphase cells, DNA is packed in a nucleus as forming nucleosome and chromatin, (b) DNA forms nucleosome structure together with core histone octamer, which is then folded up into 30nm fiber with a help of linker histone HI. This 30 nm fiber is further folded into 80 nm fiber and 300 nm loop structures in a nucleus. In mitosis, chromosome is highly condensed. Proteins which are involved in each folding step are indicated above and non-protein factors are indicated below, (c) The amino acid sequences of histone tails (H2A, H2B, H3 and H4) are shown to indicate acetylation, methylation and phosphorylation sites. (See Colour Plate 1.)...

In addition to the role for the nucleosome-nucleosome interactions, the histone tails are known as the region that undergoes post-transcriptional modifications, such as acetylation, phosphorylation, and methylation (Fig. Ic) (Peterson and Laniel, 2004). These modifications trigger the formation of euchromatin (acetylation), heterochromatin (methylation), or metaphase chromosome (phosphorylation). The details of these modifications will be described in chapters 8-11. 

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... 

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. 

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. 

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.

Histone tails can also be modified by methylatlon, phosphorylation, and monoubiquitination. These modifications influence chromatin structure by regulating the binding of histone tails to other less abundant chromatin-associated proteins. 

In addition to reversible acetylation, histone tails in chromatin can undergo reversible phosphorylation of serine and threonine residues, reversible monoublqultlnatlon of a lysine residue in the IT2A C-termlnal tall, and irreversible methy-... 

Several known covalent modifications have been observed so far that can modify the amino acid residues in the histone tails. There include acetylation, phosphorylation, ubiquitination, and methylation. Although some of these modifications have been known for many years, only recently have functional roles for these modifications begun to surface (Workman and Kingston, 1998). Each histone can undergo numerous modifications, and the combinatorial effect of these serves to elicit a multitude of different responses. This combinatorial modification of histone tails has been referred to as the histone code (Jenuwein and Allis, 2001 Strahl and Allis, 2000) and has been proposed to play a pivotal role in the regulation of gene expression (Fig. 3). 

---