Maintenance of open DNA base pairs through histone acetylated lysine-purine interaction leading to transcriptional activation: A proposed mechanism

Abstract

Post-translational acetylation of lysines of the histone N-terminal tails is known to induce transcriptional activation, and thus plays a major role in gene regulation. A mechanism for this effect is suggested by our recent finding that the initial 'solvation' network, which is formed around the purines of base pairs immediately following their opening, has the tendency to be preserved. The experiments involved studying the solvation of nucleosides in water-alcohol mixtures; these systems model the hydrophobic/hydrophilic effects that participate in the interaction between histone-tail amino acid residues and nucleosomal DNA base pairs following their opening by the action of DNA-binding proteins in conjunction with remodeling complexes. A highly amphiphilic molecular environment, which has a four-carbon aliphatic chain and hydrogen bond accepting and donating capabilities, was found to promote this phenomenon. Acetylated lysines, unlike lysines, possess these properties and thus constitute such a molecular environment. Opened base pairs are maintained by direct interactions of their purines with acetylated lysines that are selectively recognized by the bromodomains of the recruited remodeling complexes. This maintenance is in accord with the reported large enhancements of i) transcription factor binding to nucleosomal DNA and (ii) the degree of DNA flexibility, which are associated with histone-tail acetylation. This mechanism suggests a way to possibly establish an orderly sequence of transcriptional events despite the reported prevailing stochasticity. It also suggests an approach for the artificial control of transcriptional activation through the use of highly amphiphilic small molecules that would mimic the action of acetylated lysines; in view of the known association of aberrant transcription with cancer, this approach holds promise for advances in cancer etiology and treatment and represents an alternative to the approach that currently uses histone deacetylase inhibitors (some of which are in clinical trials).