G-Quadruplex DNA and RNA

Abstract

G-quadruplexes (G4s) have become one of the most exciting nucleic acid secondary structures. A noncanonical, four-stranded structure formed in guanine-rich DNA and RNA sequences, G-quadruplexes can readily form under physiologically relevant conditions and are globularly folded structures. DNA is widely recognized as a double-helical structure essential in genetic information storage. However, only ~3% of the human genome is expressed in protein; RNA and DNA may form noncanonical secondary structures that are functionally important. G-quadruplexes are one such example which have gained considerable attention for their formation and regulatory roles in biologically significant regions, such as human telomeres, oncogene-promoter regions, replication initiation sites, and 5'- and 3'-untranslated region (UTR) of mRNA. They are shown to be a regulatory motif in a number of critical cellular processes including gene transcription, translation, replication, and genomic stability. G-quadruplexes are also found in nonhuman genomes, particularly those of human pathogens. Therefore, G-quadruplexes have emerged as a new class of molecular targets for drug development. In addition, there is considerable interest in the use of G-quadruplexes for biomaterials, biosensors, and biocatalysts. The First International Meeting on Quadruplex DNA was held in 2007, and the G-quadruplex field has been growing dramatically over the last decade. The methods used to study G-quadruplexes have been essential to the rapid progress in our understanding of this exciting nucleic acid secondary structure.

Keywords: Cancer; DNA; DNA damage; Drug target; G-quadruplexes; Human diseases; Human telomeres; Oncogene promoters; RNA; Replication; Transcription; Translation; UTR.

Fig. 1

(a) Schematic illustration of a G-tetrad, four guanine bases arranged in a square plane with Hoogsteen hydrogen bonding. Monovalent cations (K⁺ or Na⁺, shown as blue spheres) are required to stabilize G-quadruplexes by coordinating with the O6 atoms of the adjacent G-tetrad planes. (b) A schematic intermolecular (tetrameric) G-quadruplex with three G-tetrads. (c) Examples of intramolecular G-quadruplexes with different folding structures and loop conformations. The experimentally determined molecular structures are shown as examples for parallel, hybrid, and basket G-quadruplexes. (d) Example NMR molecular structures of ligand complexes with the c-MYC promoter G-quadruplex and the human telomeric G-quadruplex