Histone H2A is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. The other histone proteins are: H1, H2B, H3 and H4.
Background Histones are proteins that package DNA into nucleosomes. Histones are responsible for maintaining the shape and structure of a nucleosome. One chromatin molecule is composed of at least one of each core histones per 100 base pairs of DNA. There are five families of histones known to date; these histones are termed H1/H5, H2A, H2B, H3, and H4. H2A is considered a core histone, along with H2B, H3 and H4. Core formation first occurs through the interaction of two H2A molecules. Then, H2A forms a dimer with H2B; the core molecule is complete when H3-H4 also attaches to form a tetramer.
Sequence variants Histone H2A is composed of non-allelic variants. The term "Histone H2A" is intentionally non-specific and refers to a variety of closely related proteins that vary often by only a few amino acids. Apart from the canonical form, notable variants include H2A.1, H2A.2, H2A.X, and H2A.Z. H2A variants can be explored using "HistoneDB with Variants" database Changes in variant composition occur in differentiating cells. This was observed in differentiating neurons during synthesis and turnover; changes in variant composition were seen among the H2A.1 histone. The only variant that remained constant in the neural differentiation was variant H2A.Z. H2A.Z is a variant that exchanges with conventional H2A core protein; this variant is important for gene silencing. Physically, there are small changes on the surface area of the nucleosome that make the histone differ from H2A. Recent research suggests that H2AZ is incorporated into the nucleosome using a Swr1, a Swi2/Snf2- related adenosine triphosphatase. Another H2A variant that has been identified is H2AX. This variant has a C-terminal extension that is utilized for DNA repair. The method of repair this variant employs is non-homologous end joining. Direct DNA damage can induce changes to the sequence variants. Experiments performed with ionizing radiation linked γ- phosphorylation of H2AX to double-strand breaks. A large amount of chromatin is involved with each DNA double-strand break; a response to DNA damage is the formation of γ- H2AX. Lastly, MacroH2A variant is a variant that is similar to H2A; it is encoded by the H2AFY gene. This variant differs from H2A because of the addition of a fold domain in its C-terminal tail. MacroH2A is expressed in the inactive X chromosome in females.
Structure
H2A consists of a main globular domain, an N-terminal tail and a C-terminal tail. Both tails are the location of post-translational modification. Thus far, researchers have not identified any secondary structures that arise in the tails. H2A utilizes a protein fold known as the 'histone fold'. The histone fold is a three-helix core domain that is connected by two loops. This connection forms a 'handshake arrangement.' Most notably, this is termed the helix-turn-helix motif, which allows for dimerization with H2B. The 'histone fold' is conserved among H2A at the structural level; however the genetic sequence that encodes for this structure differs between variants. The structure of macroH2A variant was exposed through X-ray crystallography. The conserved domain contains a DNA binding structure and a peptidase fold. The function of this conserved domain remains unknown. Research suggests that this conserved domain may function as an anchor site for Xist DNA or it may also function as a modifying enzyme.
Function
DNA Folding: H2A is important for packaging DNA into chromatin. Since H2A packages DNA molecules into chromatin, the packaging process will affect gene expression. H2A has been correlated with DNA modification and epigenetics. H2A plays a major role in determining the overall structure of chromatin. Inadvertently, H2A has been found to regulate gene expression. DNA modification by H2A occurs in the cell nucleus. Proteins responsible for nuclear import of H2A protein are karyopherin and importin. Recent studies also show that nucleosome assembly protein 1 is also used to transport of H2A into the nucleus so it can wrap DNA. Other functions of H2A have been seen in the histone variant H2A.Z. This variant is associated with gene activation, silencing and suppression of antisense RNA. In addition, when H2A.Z was studied in human and yeast cells, it was used to promote RNA polymerase II recruitment. Antimicrobial peptide: Histones are conserved eukaryotic cationic proteins present in the cells and are involved in the antimicrobial activities. In vertebrates and invertebrates, Histone H2A variant is reported to be involved in host immune response by acting as antimicrobial peptides (AMPs). H2A are α-helical molecule, amphipathic protein with hydrophobic and hydrophilic residues on opposing sides that enhances the antimicrobial activity of H2A.
DNA damage response Site specific ubiquitination of histone H2A has a role in the recruitment of DNA repair proteins to DNA double strand breaks which then may be repaired by either homologous recombination or non-homologous end joining. In the DNA damage response, it is thought that ubiquitination of H2A by the BRCA1/BARD1 heterodimer promotes homologous recombination, and that ubiquitination of H2A by RNF168 protein promotes non-homologous end joining.
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