Chromatin

There is a vast literature on the response of cellular systems, from bacteria to mammalian cells, but also animal and even clinical studies. In the present context, the emphasis will be on mechanistic details concerning the free-radical aspects. The most important late effects, notably the processing of DNA damage by the repair enzymes cannot be dealt with here. 

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The native form of chromatin in cells assumes a higher order stmcture called the 30-nm filament, which adopts a solenoidal stmcture where the 10-nm filament is arranged in a left-handed cod (Fig. 5). The negative supercoiling of the DNA is manifested by writhing the hehcal axis around the nucleosomes. Chromatin stmcture is an example of toroidal winding whereas eukaryotic chromosomes are linear, the chromatin stmctures, attached to a nuclear matrix, define separate closed-circular topological domains. 

Fig. 5. Solenoid model of the 30-nm filament of chromatin, where the disks represent nucleosomes and the dark line unbound DNA.

The detachment of chromatin from the nuclear scaffold, leading to chromatin conden.sation. 

Nucleus The nucleus is separated from the cytosol by a double membrane, the nuclear envelope. The DNA is complexed with basic proteins (histones) to form chromatin fibers, the material from which chromosomes are made. A distinct RNA-rich region, the nucleolus, is the site of ribosome assembly. The nucleus is the repository of genetic information encoded in DNA and organized into chromosomes. During mitosis, the chromosomes are replicated and transmitted to the daughter cells. The genetic information of DNA is transcribed into RNA in the nucleus and passes into the cytosol where it is translated into protein by ribosomes. 

The DNA in a eukaryotic cell nucleus during the interphase between cell divisions exists as a nucleoprotein complex called chromatin. The proteins of chromatin fall into two classes histones and nonhistone chromosomal proteins. 

If chromatin is swelled suddenly in water and prepared for viewing in the electron microscope, the nucleosomes are evident as beads on a string, dsDNA being the string (Figure 12.28). The structure of the histone octamer core has been determined by X-ray crystallography without DNA by E. N. Moudrianakis s laboratory (Figure 12.29) and wrapped with DNA by T. J. 

FIGURE 12.28 Electron micrograph of Drosophila melanogaster chromatin after swelling reveals the presence of nncleosomes as beads on a string. (Electron micrograph courtesy of Oscar L. Miller, Jr, of the University of Virginia)... 

Chemical approach to the study of supramolecular biological structure of chromatin, nucleoproteide complex of DNA 99UK365. 

Chromatin is a noncovalent complex consisting of DNA and dedicated packing proteins, the histones. The name chromatin is derived from the Greek word chroma... 

Chromatin is composed of nucleosomes, where each comprise 147 base pairs of DNA wrapped around an octamer oftwo copies of each histone H2A, H2B, H3, and H4. Nucleosomes are folded into higher-order structures that are stabilized by linker histones. Chromatin structure can be altered by enzymes that posttranslationally modify histones (e.g., through phosphorylation, acetylation, methylation, or ubiquitination) or by ATP-driven chromatin-remodeling complexes that alter nucleosome position and/or composition. 

The antagonist-induced conformation of nuclear hormone receptors attracts co-repressors like Nco/SMRT (nuclear hormone receptor co-repressor/silencing mediator of retinoid and thyroid receptors) which further recruit other nuclear proteins with histone deacetylase activity. Their action leads to chromatin condensation, thus preventing the general transcription apparatus from binding to promoter regions. 

DNA fragmentation occurs in two stages. Firstly, endonucleolytic activity cleaves the DNA into high molecular weight fragments leading to the morphological picture of chromatin condensation characteristic... 

Due to the large amount of DNA present within the nucleus it must be carefully packaged. In the resting cell DNA is tightly compacted around basic histone proteins, excluding the binding of the enzyme RNA polymerase II, which activates the formation of mRNA. This conformation of the chromatin structure... 

Repression of genes is associated with reversal of this process under the control of histone deacetylases (HDACs). Deacetylation of histones increases the winding of DNA round histone residues, resulting in a dense chromatin structure and reduced access of transcription factors to their binding sites, thereby leading to repressed transcription of inflammatory genes. 

Histones are small, basic proteins required to condense DNA into chromatin. They have been first described and named in 1884 by Albrecht Kossel. There are five main histones HI, H2A, H2B, H3 andH4. An octamer of core histones H2A, H2B, H3 andH4 is located inside a nucleosome, the central building block of chromatin, with about 150 base pairs of DNA wrapped around. The basic nature of histones, mediated by the high content of lysine and arginine residues, allows a direct interaction with the acidic phosphate back bone of DNA. The fifth histone HI is located outside at the junction between nucleosomes and is referred to as the linker histone. Besides the main histones, so-called histone variants are known, which replace core histones in certain locations like centromers. 

An enzyme activity ascribed to many coactivators, which transfers acetyl groups to lysine residues of histone tails of the nucleosomes and thereby facilitate their disruption and the opening of the chromatin. 

Histone acetylation is a reversible and covalent modification of histone proteins introduced at the e-amino groups of lysine residues. Histones and DNA form a complex - chromatin - which condenses DNA and controls gene activity. Current models interpret histone acetylation as a means to regulate chromatin activity. 

A model called histone code theory includes more aspects of chromatin regulation which have been identified. The histone code theory predicts that histone acetylation and other posttranslational histone modifications serve as binding sites for regulatory proteins which mediate processes like gene transcription upon recruitment (see Fig. 2b) [3]. In this context histone modifications can be understood as... 

The exact role of individual histone acetylations will have to be determined in the context of other modifications and the number of lysine residues effected. However, the general importance of histone acetylation as a regulator for chromatin activity is undisputed. This leads to the intriguing possibility to develop drugs that target histone acetylation for therapeutic purposes. The primary targets for drug development are the histone acetyl transferases (HATs) and the histone deacetylases (HDACs) which introduce and remove histone acetylations [2, 3]. 

Like HATs, most functional HDACs are embedded in large multifunctional protein complexes, which also contain other chromatin modifying enzymes and coregulator proteins [1]. 

Turner BM (2001) Chromatin and Gene Regulation. Blackwell Science Ltd., Oxford... 

Enzyme activity ascribed to corepressors, which is the removal of acetyl groups from lysine residues of histone tails. Thereby the assembly of nucleosomes is maintained, which leads to a dense, transcriptional inactive chromatin structure. 

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. 

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