ДНҚ-ны орап тұратын гистонды протеиндер отбасысы

Protein family around which DNA winds to form nucleosomes

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30 nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers. There are five families of histones which are designated H1/H5 (linker histones), H2, H3, and H4 (core histones). The nucleosome core is formed of two H2A H2B dimers and a H3 H4 tetramer. The tight wrapping of DNA around histones is to a large degree a result of electrostatic attraction between the positively charged histones and negatively charged phosphate backbone of DNA. Histones may be chemically modified through the action of enzymes to regulate gene transcription. The most common modification are the methylation of arginine or lysine residues or the acetylation of lysine. Methylation can affect how other protein such as transcription factors interact with the nucleosomes. Lysine acetylation eliminates a positive charge on lysine thereby weakening the electrostatic attraction between histone and DNA resulting in partial unwinding of the DNA making it more accessible for gene expression.

Core histones are found in the nuclei of eukaryotic cells and in most Archaeal phyla, but not in bacteria. but later studies showed that their DNA still encodes histone genes. Unlike the core histones, homologs of the lysine rich linker histone (H1) proteins are found in bacteria, otherwise known as nucleoprotein HC1/HC2. It has been proposed that core histone proteins are evolutionarily related to the helical part of the extended AAA+ ATPase domain, the C domain, and to the N terminal substrate recognition domain of Clp/Hsp100 proteins. Despite the differences in their topology, these three folds share a homologous helix strand helix (HSH) motif. It's also proposed that they may have evolved from ribosomal proteins (RPS6/RPS15), both being short and basic proteins. Archaeal histones may well resemble the evolutionary precursors to eukaryotic histones. Histone proteins are among the most highly conserved proteins in eukaryotes, emphasizing their important role in the biology of the nucleus. There are some variant forms in some of the major classes. They share amino acid sequence homology and core structural similarity to a specific class of major histones but also have their own feature that is distinct from the major histones. These minor histones usually carry out specific functions of the chromatin metabolism. For example, histone H3 like CENPA is associated with only the centromere region of the chromosome. Histone H2A variant H2A. Z is associated with the promoters of actively transcribed genes and also involved in the prevention of the spread of silent heterochromatin. Furthermore, H2A. Z has roles in chromatin for genome stability. Another H2A variant H2A. X is phosphorylated at S139 in regions around double strand breaks and marks the region undergoing DNA repair. Histone H3.3 is associated with the body of actively transcribed genes.

Histones act as spools around which DNA winds. This enables the compaction necessary to fit the large genomes of eukaryotes inside cell nuclei: the compacted molecule is 40,000 times shorter than an unpacked molecule.

A huge catalogue of histone modifications have been described, but a functional understanding of most is still lacking. Collectively, it is thought that histone modifications may underlie a histone code, whereby combinations of histone modifications have specific meanings. However, most functional data concerns individual prominent histone modifications that are biochemically amenable to detailed study.

The addition of one, two, or many methyl groups to lysine has little effect on the chemistry of the histone; methylation leaves the charge of the lysine intact and adds a minimal number of atoms so steric interactions are mostly unaffected. However, proteins containing Tudor, chromo or PHD domains, amongst others, can recognise lysine methylation with exquisite sensitivity and differentiate mono, di and tri methyl lysine, to the extent that, for some lysines (e. g.: H4K20) mono, di and tri methylation appear to have different meanings. Because of this, lysine methylation tends to be a very informative mark and dominates the known histone modification functions.

Recently it has been shown, that the addition of a serotonin group to the position 5 glutamine of H3, happens in serotonergic cells such as neurons. This is part of the differentiation of the serotonergic cells. This post translational modification happens in conjunction with the H3K4me3 modification. The serotonylation potentiates the binding of the general transcription factor TFIID to the TATA box.

What was said above of the chemistry of lysine methylation also applies to arginine methylation, and some protein domains—e. g., Tudor domains—can be specific for methyl arginine instead of methyl lysine. Arginine is known to be mono or di methylated, and methylation can be symmetric or asymmetric, potentially with different meanings.

Enzymes called peptidylarginine deiminases (PADs) hydrolyze the imine group of arginines and attach a keto group, so that there is one less positive charge on the amino acid residue. This process has been involved in the activation of gene expression by making the modified histones less tightly bound to DNA and thus making the chromatin more accessible. PADs can also produce the opposite effect by removing or inhibiting mono methylation of arginine residues on histones and thus antagonizing the positive effect arginine methylation has on transcriptional activity.

Addition of an acetyl group has a major chemical effect on lysine as it neutralises the positive charge. This reduces electrostatic attraction between the histone and the negatively charged DNA backbone, loosening the chromatin structure; highly acetylated histones form more accessible chromatin and tend to be associated with active transcription. Lysine acetylation appears to be less precise in meaning than methylation, in that histone acetyltransferases tend to act on more than one lysine; presumably this reflects the need to alter multiple lysines to have a significant effect on chromatin structure. The modification includes H3K27ac.

Addition of a negatively charged phosphate group can lead to major changes in protein structure, leading to the well characterised role of phosphorylation in controlling protein function. It is not clear what structural implications histone phosphorylation has, but histone phosphorylation has clear functions as a post translational modification, and binding domains such as BRCT have been characterised.

Most well studied histone modifications are involved in control of transcription.

Phosphorylation of H3 at serine 10 (phospho H3S10) The mitotic kinase aurora B phosphorylates histone H3 at serine 10, triggering a cascade of changes that mediate mitotic chromosome condensation. Condensed chromosomes therefore stain very strongly for this mark, but H3S10 phosphorylation is also present at certain chromosome sites outside mitosis, for example in pericentric heterochromatin of cells during G2. H3S10 phosphorylation has also been linked to DNA damage caused by R loop formation at highly transcribed sites. Phosphorylation H2B at serine 10/14 (phospho H2BS10/14) Phosphorylation of H2B at serine 10 (yeast) or serine 14 (mammals) is also linked to chromatin condensation, but for the very different purpose of mediating chromosome condensation during apoptosis. This mark is not simply a late acting bystander in apoptosis as yeast carrying mutations of this residue are resistant to hydrogen peroxide induced apoptotic cell death.

Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions. Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions. After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the nucleus accumbens of the brain, causing 61% increase in FosB expression. This would also increase expression of the splice variant Delta FosB. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction. About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol. Methamphetamine addiction occurs in about 0.2% of the US population. Chronic methamphetamine use causes methylation of the lysine in position 4 of histone 3 located at the promoters of the c fos and the C C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc). c fos is well known to be important in addiction. The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction. Suppression of histone gene expression outside of S phases is dependent on Hir proteins which form inactive chromatin structure at the locus of histone genes, causing transcriptional activators to be blocked.

In metazoans the increase in the rate of histone synthesis is due to the increase in processing of pre mRNA to its mature form as well as decrease in mRNA degradation; this results in an increase of active mRNA for translation of histone proteins. The mechanism for mRNA activation has been found to be the removal of a segment of the 3' end of the mRNA strand, and is dependent on association with stem loop binding protein (SLBP). SLBP also stabilizes histone mRNAs during S phase by blocking degradation by the 3'hExo nuclease. SLBP levels are controlled by cell cycle proteins, causing SLBP to accumulate as cells enter S phase and degrade as cells leave S phase. SLBP are marked for degradation by phosphorylation at two threonine residues by cyclin dependent kinases, possibly cyclin A/ cdk2, at the end of S phase. Metazoans also have multiple copies of histone genes clustered on chromosomes which are localized in structures called Cajal bodies as determined by genome wide chromosome conformation capture analysis (4C Seq).

Nuclear protein Ataxia Telangiectasia (NPAT), also known as nuclear protein coactivator of histone transcription, is a transcription factor which activates histone gene transcription on chromosomes 1 and 6 of human cells. NPAT is also a substrate of cyclin E Cdk2, which is required for the transition between G1 phase and S phase. NPAT activates histone gene expression only after it has been phosphorylated by the G1/S Cdk cyclin E Cdk2 in early S phase. This shows an important regulatory link between cell cycle control and histone synthesis.

Histones were discovered in 1884 by Albrecht Kossel. The word "histone" dates from the late 19th century and is derived from the German word "Histon", a word itself of uncertain origin, perhaps from Ancient Greek ἵστημι (hístēmi, “make stand”) or ἱστός (histós, “loom”). In the early 1960s, before the types of histones were known and before histones were known to be highly conserved across taxonomically diverse organisms, James F. Bonner and his collaborators began a study of these proteins that were known to be tightly associated with the DNA in the nucleus of higher organisms. Bonner and his postdoctoral fellow Ru Chih C. Huang showed that isolated chromatin would not support RNA transcription in the test tube, but if the histones were extracted from the chromatin, RNA could be transcribed from the remaining DNA. Their paper became a citation classic. Paul T'so and James Bonner had called together a World Congress on Histone Chemistry and Biology in 1964, in which it became clear that there was no consensus on the number of kinds of histone and that no one knew how they would compare when isolated from different organisms. For example, they found Histone IV sequence to be highly conserved between peas and calf thymus. Until the early 1990s, histones were dismissed by most as inert packing material for eukaryotic nuclear DNA, a view based in part on the models of Mark Ptashne and others, who believed that transcription was activated by protein DNA and protein protein interactions on largely naked DNA templates, as is the case in bacteria. During the 1980s, Yahli Lorch and Roger Kornberg showed that a nucleosome on a core promoter prevents the initiation of transcription in vitro, and Michael Grunstein demonstrated that histones repress transcription in vivo, leading to the idea of the nucleosome as a general gene repressor. Relief from repression is believed to involve both histone modification and the action of chromatin remodeling complexes. Vincent Allfrey and Alfred Mirsky had earlier proposed a role of histone modification in transcriptional activation, regarded as a molecular manifestation of epigenetics. Michael Grunstein and David Allis found support for this proposal, in the importance of histone acetylation for transcription in yeast and the activity of the transcriptional activator Gcn5 as a histone acetyltransferase. The discovery of the H5 histone appears to date back to the 1970s, and it is now considered an isoform of Histone H1.