Term Paper: Histone H2AX

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Histone H2AX

In the study of biology, histones are the main, large and organic compounds made of amino acids that are considered as among the most important elements of chromatin. Chromatin is the compound and compact form of deoxyribonucleic acid (DNA) in the nucleus that makes up chromosomes. Let us focus our study to one of the major and core histones, the DNA that wraps the nucleosome around two copies each of histone proteins, the H2AX. Histone H2AX is characterized by having a long terminal tail on one end of the amino acid structure. This feature tells its main difference from H2A.

Once the DNA is damaged and its physiology is disturbed in normal healthy individual, the p53 protein or TP53 is activated and can start a cell cycle arrest. The tail of H2XA, also known as the carboxy terminus, rapidly becomes labeled with phosphate groups that generate species called gamma-H2AX. This protein functions as a tumor suppressor and protects the genes as it is closely controlled by phosphorylation. The phosphorylated histone H2AX cooperates in repairing the genetic damage. It preserves the stability of the cells and prevents the onset of tumors. In DNA repair, chromatic reorganization plays an important role. Chromatin is responsible in packaging the DNA into a smaller volume for it to fit in the cell. This process aims to strengthen the DNA to allow mitosis and meiosis, where the cells divides and separates into two identical sets. This is also vital in apoptosis, cell cycle checkpoints, and serves as a mechanism to control inheritable information from a gene. The H2AX histone phosphorylation kinetics correlated well with the kinetics of DNA-adducts removal at earlier recovery time points. The chromatin reorganization is composed of proteins that are involved in the process. Among these proteins is TIP60 histone acetyltransferase, which plays an important role in DNA repair and apoptosis.

Conversely, its function to regulate the chromatin reorganization in the response of human cells to DNA damage is not commonly known. Based on microscopic studies, gamma-H2AX is generated in the chromatic edging a DNA double-strand break, and signaling proteins are recruited to the sites, known as "foci." TIP60 normalizes the ubiquitination of H2AX by means of the ubiquitin-conjugating enzyme UBC13, which is largely induced by DNA damage. To continue the process, this ubiquitination of H2AX requires its prior acetylation. Researches show that aceylation-dependent ubiquitination by the TIP60-UBC13 complex leads to the release of H2AX from damaged chromatin.

It was concluded that the sequential acetylating and ubiquitination of H2AX by TIP60-UBC13 promote enhanced histone dynamics, which in turn stimulate a DNA damage response (ESR Nexus Medical Research Community). Please note that the gamma-H2AX is not that essential in the recruitment of the repair factors, but indeed in the later formation of the foci. If the DNS damage proves to be irreparable, p53 can initiate apoptosis or a programmed cell morphology and death. The p53 status of the cell determines the decision between life or death after genotoxic stress.

Tornaletti et al. conducted a detailed investigation of how nucleosomes are formed and arranged on the DNA sequence in order to better understand the molecular mechanism if DNA-dependent processes such as transcription, replication, DNA repair, and mutagenesis. In their report, they analyzed the chromatin structure of exons 5-8 of the p53 gene in human fibroblasts. They also mapped at the nucleotide level the positions of DNase I and microccocal nuclease cleavage sites in pemeabilized cells. Areas of clear DNAse I protection, which would be indicative of the binding of sequence-specific proteins, were not detected. Instead, the micrococcial nuclease and DNase digestion patterns suggested that the region was covered by nucleosomes and that two areas spanning exons 5 and 6 are occupied preferentially. These nucleosomes could influence DNA damage distribution, repair of certain lesions, and other aspects of the mutagenesis process in p53 sequences.

Now, let us take a look at histone, as a gene or protein in the aquatic environment. Aquatic plants are very diverse and encompass the kingdoms Bacteria, Archaea, Protista, Fungi, and Plantae. The cells of cyanobacteria are typically small and composed of single DNA and circular molecule lacking histones as basic proteins. They do not have membrane bound-organelles. Eukaryotic algae have not much larger cells. Their DNAs are organized into one or more chromosomes, including histones. There are various membrane-bound organelles in nucleus. Histone H2A is a component of eukaryotic chromatin whose expression has not been studied in plants. To identify the cell-specific expression of plant histone to H2A genes, Koning et al. isolated and characterized a tomato and a pea cDNA encoding histone H2A. They found that in tomato H2A is encoded by a small gene family and that both the pea and the tomato mRNAs are polyadenylated. Tomato H2A has 82 amino acid residue identity to pea H2A, 83% to wheat, and 65% to human and yeast H2A. Plant H2As differ from fungal and animal H2As in their amno-terminal and carboxy-terminal regions. Carboxy-terminal plant H2A regions contain the motif SPKK, a peptide implicated in binding of a/T-rich DNA regions. By using RNA gel blot analysis, the authors determined that the steady-state mRNA level of these genes was abundant in apices and early developing fruit and very low in mature tissues. They also found that in situ RNA hybridization showed strong spatial regulation because the mRNA was abundant in some cells and not detectable in others. In tomato root tips, H2A-expressing cells were distributed irregularly in or near meristems. In tomato or pea root tips, expressing cells were concentrated near the apex, and their distribution was consistent with that expected of cycling cells. The authors also found other H2A transcripts in nondividing cortical cells that are known to undergo endoduplication during late maturation phase of primary development (1991)

In PubMed Central's article, Busslinger et al. talked about the histone DNA clone h19 of the sea urchin Psammechinus miliaris. It was found that in clone h19 of polarity of transcription and the relative arrangement of the histone genes is identical to that in clone h22 of the same species. The histone proteins encoded by h19 DNA differ in their primary structure from those encoded by clone h22 and have been compared to histone protein sequences of other sea urchin species a well as other eukaryotes.

The transcription of the sea urchin early histone genes occurs transiently during early cleavage, reaching the maximum at the morula stage and declining to an undetectable level at the gastrula stage. To identify the regulatory elements responsible for the timing and the levels of transcription of the H2A gene, promoter binding studies in nuclear extracts and microinjection of a CAT transgene driven y the early H2A promoter was used. It was found out that morula and gastrula nuclear proteins produced indistinguishable NDase I footprint patterns on the H2A promoter. There were two sites of interactions, centered on the modulator/enhancer and on the CCAAT box respectively, were detected. Deletion of the modulator or coinjection of an excess of modulator sequences severely affected the expression of two transgenes driven by the enhancer-less and modulator-containing H2A promoter. Finally, a DNA fragment containing 3' coding and post-H2A spacer sequences, where upon silencing three micrococcal nuclease hypersensitive sites were previously mapped, specifically repressed at the gastrula stage the expression of the transgene driven by the H2A promoter. These results indicate that the modulator for the expression of early H2A gene and that sequences for downregulation are localized near the 3' end of the H2A gene (Palla et al.: 1999).

The aquatic environment exposes both human and animal life to the presence of bacteria and other forms of parasites like entamoeba. Entamoeba belongs to the genus of amoebozoa that is usually found as internal parasites of animals. Some of its species are found in humans; and species of E. moshkovskii are found from river and lake sediments. The pathogen that is responsible for amoebiasis is called Entamoeba histolytica.

During the 5th Annual Congress on Tropical Medicine and International Health, among the topics discussed was the silencing of gene expression. One of their purposes is to study the role of histone acetylation in the regulation of E. histolytica. This was done through methylated cytosine that recruits methylated CpG binding proteins that interact with histonedeacetylase to alter the chromatin. In most eukararyotes such as animals, plants, and fungi whose cells are organized into complex structures enclosed within membranes, the cytosines are methylated by DNA methyltransferases that belong to the DNMT1 and DNMT3 families. In the parasite Entamoeba histolytica, the formation of methylated cystosine is catalyzed by an unexpected DNA methyltransferase from the DNMT2 family. The targets of methylated comprise LINE retrotransposon, rDNA and S/MAR element which suggests that methylation plays a role in the control of repetitive elements. In their study, they recently identified a protein, EhMLBP, that binds with high affinity to methylated INE retrotransposon and rDNA. EhMLBP lacks homology with methyl-CpG binding proteins and it shares a weak sequence identity with several prokaryotic histone. To further their study about recombinational DNa… [END OF PREVIEW]

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