Histone proteins mechanism

In the nuclei of all eukaryotic cells, DNA is tightly wrapped around an octamer of histone proteins and is compacted into a dense structure known as chromatin. In order to access the genetic information which is required in numerous essential cellular processes including DNA replication, gene expression and DNA repair, chromatin needs to be partially unwound. One important mechanism to regulate chromatin structure and thus to control the access of the genomic DNA is through histone modifications [1-6]. The histone octamer is composed of two copies of H2A, H2B, H3 and H4 core histone proteins. Their tails, that protrude out of the surface of the... 

Cell cycle progression, apoptosis, DNA damage and DNA repair are cellular functions that are regulated by several mechanisms. One such important regulatory mechanism is posttranslational modification of histone and non-histone proteins. Myriad of reports have been shown that acetylation of non-histone proteins apart from histones, contributes in major to these processes. 

Regulation of transcription is a central mechanism by which cells respond to developmental and environmental cues. RNA polymerase Il-mediated transcription in eukaryotes is to a large extent regulated at the level of chromatin, which forms a physical barrier for the binding of proteins to the promoter region of a target gene. The basic unit of chromatin is the nucleosome, which consists of an octamer of histone proteins around which the DNA is wrapped (see Fig. la). 

Jackson MD, Schmidt MT, Oppenheimer NJ, Denu JM (2003) Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J Biol Chem 278(51) 50985-50998 Johnstone RW, Licht JD (2003) Histone deacetylase inhibitors in cancer therapy Is transcription the primary target Cancer Cell 4 13-18... 

There are two major mechanisms of epigenetic regulation, methylation of cytosines in the DNA sequence and modification of the histone proteins that the DNA is wrapped around. The co-ordination of both mechanisms results in dramatic changes in remodeling of chromatin and altered gene transcription. 

Chromatin is the complex combination of DNA, RNA and protein that makes up chromosomes inside the nuclei of eukaryotic cells it is divided between heterochromatin (condensed) and euchromatin (extended) forms. The functions of chromatin are to package DNA into a smaller volume to fit into the cell, to support the DNA to allow mitosis and meiosis, and to serve as a mechanism to control expression and DNA replication. Changes in chromatin strncture are affected by chemical modifications of histone proteins, such as methylation (DNA and proteins) and acetylation (proteins), and by non-histone DNA-binding proteins. Chromatin is easily visualised by staining, hence its name, which literally means coloured, lightened material. 

Acetylation and deacetylation of lysine residnes on histone proteins provide one mechanism by which transcription can be activated or repressed. Which one of the histone proteins is least likely to participate in this process ... 

Although a precise definition of the role of nuclear poly(ADP-ribosyl)ation is not available, the histone-shuttle mechanism proposed by Althaus and colleagues offers a possible unifying explanation of numerous experimental findings. While this model will come under further experimental scrutiny, the effects of ADP-ribo-sylating individual chromosomal proteins other than the polymerase itself (automodification) still needs to be elucidated. 

Protein phosphorylation is a pervasive posttranslational modification in cells. It is reversible and can dramatically affect the activity of a modified protein. Protein phosphorylation is one of the most important mechanisms used for signal transduction by cells. In prokaryotic cells, the best-known reversible protein phosphorylations occur on histidine and aspartate in eukaryotes the best-known occur on the hydroxyl groups of serine, threonine, and tyrosine, although histidine can also be phosphorylated (Fig. 3.9). Other reversible modifications also occur, such as the acetylation of lysine residues in histone proteins. 

An additional cardinal regulatory mechanism of differential control of gene expression is chromatin structure. In eukaryotic cells, DNA is not naked but is packaged into nucleosomes, subunits of chromatin in which short tracts of DNA are wrapped around a core of histone proteins. As a consequence, accessibility of RNAP II and regulatory transcription factors to DNA is limited. More often than not, in the presence of a stable, inaccessible chromatin structure (heterochromatin), transcription is repressed, whereas the formation of an open accessible chromatin structure (euchromatin) is transcribed. ... 

This theory most directly applies to carcinogenesis induced by Ni(ll), since Ni(ll) binds preferentially to histones (proteins of the cell nucleus) rather than to DNA (354—373). The Ni -protein complexes can then catalyze oxidative DNA damage by ROS (149). Catalytic rather than stoichiometric action of Ni(ll) complexes in oxidative DNA damage is consistent with significant genotoxic effects caused by small concentrations of the metal ion (350-368). Indirect (i.e., ROS mediated) oxidative mechanisms are also considered among the major causes of Cd(ll) and Cr(Vl) induced carcinogenicity (351, 353). 

The identities of several protein arginine methyltransferases are now known, but only a few have been shown to have specificity for histone proteins. The mammalian PRMT1, JBP1, and CARMI, as well as the Saccharomyces Rmtl, have histone methyltransferase activity (McBride and Silver, 2001). However, the catalytic mechanism for the methyl group transfer as well as the makeup of the active sites of PRMTs differ somewhat from SET domain proteins. 

Histone deacetylases (HDACs, EC number 3.5.1) remove acetyl groups from A -acetyl lysines by hydrolysis, both on histones and non-histone proteins, hence are more generally referred to as lysine deacetylases (KDACs). HDACs are grouped into four classes based on sequence homology and mechanism (Table 5.2). The first two classes, sometimes referred to as classical HDACs, are zinc-dependent and their activity is inhibited by hydroxamic acids, e.g. trichostatin A (TSA). The third class, referred to as Sirtuins, are NAD -dependent proteins and are not inhibited by TSA. The fourth class is also zinc-dependent, but is considered an atypical category based on low sequence homology to classes I and II. Class I and IV HDACs are mainly found in the nucleus and are expressed in many cell types, while the expression of class II HDACs, which are able to shuttle in and out of the nucleus, is tissue specific. Sirtuin localisation depends on the particular isoform (cytoplasm, mitochondria and nucleus). 

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