Gquadruplexes

G-quadruplexes, or G4 structures, are noncanonical nucleic acid secondary structures formed in guanine-rich sequences. They arise when guanine bases associate through Hoogsteen hydrogen bonds to form planar G-tetrads, which can stack on top of each other to create a four-stranded configuration. Each G-tetrad consists of four guanines, and several tetrads stack to give a stable G-quadruplex. Cations, notably potassium, stabilize the stacked tetrads and promote formation.

G-quadruplexes can be intramolecular, formed by a single strand that folds back on itself, or intermolecular, formed from two or four strands. Depending on the loops that connect the guanine runs, G4s can adopt parallel, antiparallel, or hybrid topologies. RNA G-quadruplexes commonly adopt parallel structures; DNA G4s can be parallel, antiparallel, or hybrid, with topology influenced by sequence and ionic conditions.

G-quadruplex formation is favored by negative supercoiling during replication and transcription, and by cellular ions. In vitro evidence comes from NMR, X-ray crystallography, circular dichroism, and chemical footprinting. A range of small molecules, including telomestatin and certain porphyrins, bind and stabilize G4s, enabling study and potential therapy.

Biological relevance: G4 motifs are enriched in telomeres, promoters, and untranslated regions, implicating roles in transcriptional regulation, replication, telomere maintenance, and genome stability. In RNA, G4s can regulate translation initiation and mRNA localization, and are substrates for various helicases and binding proteins. Because they can modulate critical processes, G4s are investigated as therapeutic targets in cancer and viral infections.

Despite progress, G-quadruplex biology is complex; in vivo formation is dynamic and context-dependent, and not all predicted G4-forming sequences form stable structures in cells. Detection remains challenging, and off-target effects of ligands must be considered.