The G-force in the genome: Unknowns on the functional flairs of DNA G-quadruplexes

Alternative DNA secondary structures known as G-quadruplexes (G4s) form across all kingdoms of life, regulating transcription, telomere stability, and genome maintenance. Although many putative G4-forming sequences are predicted to exist, it remains unclear which ones fold in cells at any given time and what mechanisms drive their formation. Moreover, while G4s have been primarily linked to transcriptional regulation, how this function is achieved remains to be investigated, and the roles of G4s at other genomic regions remain unclear. This Unsolved Mystery discusses key gaps in our understanding of G4 formation and function and highlights recent mechanistic and methodological advances that are beginning to address them.