Konan University, Japan
The World of Non-canonical Nucleic Acids
Nucleic acids are excellent at recognizing complementary sequences through the formation of Watson－Crick base pairs. Since the base pairing enables the highly selective hybridization with a target sequence, synthetic DNA and RNA oligonucleo- tides are regarded as some of the most promising materials for therapeutic and diagnostic purposes, including human gene regulation, gene expression analysis, and target molecule sensing. In particular, clinical applications have provided many successes in target-specific gene regulations for the treatments of cancers, cardiovascular disease, and inflammatory diseases. Quantitative data of nucleic acid interactions are very useful for improving a number of oligonucleotide technologies. The strengths of the interbase hydrogen bonding and base stacking determine the hybridization efficiency and stability of nucleic acid structures; however, considerations of the hydration and counterion condensation are also important because water and cations associate with the polar purine and pyrimidine bases and the negatively charged sugar－phosphate backbone. Since the base pair formation is accompanied by the association or dissociation of ions and water molecules, nucleic acid interaction energies are significantly influenced by the solution composition. The stability of the Watson－Crick base pairing has been extensively studied using aqueous dilute solutions containing salts. These thermodynamic data allow the accurate predictions of the hybridization energy and secondary structures of a given sequence.
However, non-canonical structures of nucleic acids such as a triplex and a quadruplex are stabilized under conditions that mimic the crowded cellular conditions and have been detected in cells. In vitro and in vivo, guanine-quadruplex (G-quadruplex or G4) formation inhibits transcription and translation of template nucleic acids. It is possible that the non-canonical structures act as “functional codes” triggered by different molecular environments that regulate gene expression epigenetically. We reported effects of the non-canonical structures of DNA and RNA on the gene expression. As sequences capable of forming the non-canonical structures are found in telomeres and promoter regions of known oncogenes, alterations of the non-canonical structures could play important roles in the progression of cancer and in other diseases.
In this lecture I will discuss how the structures, topologies, and functions of nucleic acids differ under various conditions such as highly crowded environments and affect the replication, transcription, and translation.