DNA G-quadruplexes: Structural and functional insights

Guanine-rich regions in the human genome have the intrinsic ability to fold into G-quadruplex (G4) secondary structures, stabilized by stacked guanine quartets. There is considerable biochemical and structural evidence demonstrating formation of G4 structures in vitro under biomimetic conditions. Recently, emerging studies have also provided compelling data that authenticates the existence of these DNA G4 structures in vivo. These G4 structures, present in both DNA and RNA, are involved in key biological processes such as transcription, replication and the maintenance of genomic integrity. They have also been linked to different diseases. Given their association with multiple proteins across the DNA repair machinery, G4 structures are particularly prominent in various cancers and have been recognized as promising targets for therapeutic research. In this review, we first highlight the identification, structure and conformations of DNA G4s. We then discuss the influence of biomimetic microenvironment on G4 formation and its implication for genome function and maintenance. Next, we elaborate on the genome-wide occurrence of G4s and their roles in transcription, replication, and DNA repair. Furthermore, we explore drug design strategies aimed at selectively targeting the G4 structures and emphasize the potential of DNA G4s in cancer therapy, particularly in the context of synthetic lethality. Finally, we discuss recent advances and emerging roles of G4 biology that potentially explore new avenues of research. Taken together, this review aims to provide a comprehensive overview of DNA G4 structure and function, accentuate its role in genome maintenance and underscore their significance in cancer research.