Cell and Molecular Biology
Histones; Acylations; Lysine residues
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In order to package the entire genome into a eukaryotic cell nucleus, structures called ‘nucleosomes’ assist in condensing DNA into chromatin. Nucleosomes are composed of histones, which are the most conserved proteins currently known. There are four main types of histones (H2A, H2B, H3, H4) existing in pairs and serving as the nucleosome subunits that drive binding of DNA and formation of condensed chromatin structure. Condensed DNA in the form of chromatin is thus able to fit all of the cell’s genetic material into the nucleus. However, this compaction acts as a barrier for proteins that need to bind to linear DNA for replication, repair, and transcription. In order to unravel a cell’s DNA for mRNA synthesis, chemical modifications are added to histone tails that result in making DNA accessible. These post-translational modifications, known as histone modifications, add carbon-contain chains to the histones.
While there are several histone modifications that have been extensively studied, this review will focus on histone acetylation, succinylation, butyrylation, β-hydroxybutyrylation, crotonylation, malonylation, lactylation and hydroxylation. These histone modifications are known as ‘acylations’, covalently linked to lysine residues on flexible N-terminal histone tails. The addition of an acyl group blocks the interaction of the positively charged lysine residue with DNA, by reducing the affinity to the negatively charged phosphates on DNA. As a result, the DNA is exposed for transcription factors, allowing mRNA synthesis. Each histone acylation is a different carbon-containing compound derived from metabolic intermediates that occur within cells. For example, histone acetylation is commonly derived from the intermediate acetyl- coenzyme A (acetyl-CoA), which links glycolysis to the citric acid cycle. Acetyl-CoA is used by the enzymes called histone acetyltransferase that add acetyl groups to histones. These groups can be removed by histone deacetylases to allow rewinding of the DNA on histones. This regulation allows histone acetylations to actively control gene expression in cells. Other histone modifications operate under similar principles, but vary in structure, enzymes involved, and in their overall spatio-temporal biological roles. The study of histone acylations provides an improved understanding of gene expression and advances our knowledge of pathologies such as cancer.