The Structure and Function of DNA G-Quadruplexes

Abstract

Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery. Beyond the DNA Double HelixA chemist's perspective on the function of a molecule, or a system of molecules, is typically led by a consideration of how molecular structure dictates function. The most widely recognised DNA structure is that of the classical DNA double helix [1], which defines a structural basis for the genetic code via defined base-pairing. Yet, it is evident that DNA is structurally dynamic and capable of adopting alternative secondary structures. One such class of DNA secondary structure is the four-stranded Gquadruplex (G4). Herein, we discuss some of the key scientific history that has shaped our understanding of this structural motif, its probable functions in biology, and major unanswered questions that remain to be solved.

Structure Validation of G‐Rich RNAs in Noncoding Regions of the Human Genome

“…The strong stacking interactions between the tetrads lead to a remarkable thermodynamic stability, with the stability of RNA G‐quadruplexes exceeding that of DNA G‐quadruplexes . DNA G‐quadruplexes can be detected in vivo and their fundamental role in telomere maintenance as well as in gene regulation is generally acknowledged . Bioinformatics and in vitro studies suggested the presence of G‐rich putative quadruplex‐forming sites in untranslated regions (UTRs) of mRNAs, as well as in the transcripts of human telomers known as telomeric repeat‐containing RNA.…”

Whole genome identification of potential G-quadruplexes and analysis of the G-quadruplex binding domain for SARS-CoV-2

“…1B) on top of each other, in which the four guanines making up a G-quartets are connected via Hoogsteen pairs (Fig. 1C) [25][26][27][28]. Extensive research indicated that G-quadruplexes were involved in many critical biological processes, including DNA replication [29][30][31][32], telomere regulation [33][34][35][36][37], and RNA translation [38][39][40][41].…”

Origin, Diversity, and Evolution of Telomere Sequences in Plants

“…The minisatellite arrangement originates from the way in which telomerase synthesizes the DNA, in short, and mostly identical motifs, one by one. Several hypotheses consider that such an arrangement is important because it promotes the recognition of telomere specific proteins by homo-and heterodimers [e.g., (Hofr et al, 2009;Visacka et al, 2012)] and for the potential to form G-quadruplexes that may stabilize chromosome ends or serve as substrates for telomere-specific proteins (Spiegel et al, 2020;Tran et al, 2013). Telomere sequences are well conserved through evolution, and large groups of organisms use the grouptypical telomere motif to build their telomere DNA.…”