G‐Quadruplexes (G4s)

Abstract

Guanine‐rich regions of nucleic acids can fold into G‐quadruplex, a secondary structure formed by four strands of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). In the G‐quadruplex, guanines bind via Hoogsteen hydrogen bonds to yield the G‐quartet. Two or more G‐quartets stack on top of each other to form the G‐quadruplex, which can adopt different conformations, based both on the nature and orientation of the strands and on environmental factors such as cations. Both DNA and RNA G‐quadruplexes are found in biological systems: They have been computationally predicted and experimentally demonstrated by several methods in the genomes of several organisms, including humans, other eukaryotes, bacteria and viruses. G‐quadruplexes in the human cell genome are found in pivotal genomic regions, where they mainly act as regulatory elements. Several proteins process the G‐quadruplex. G‐quadruplex ligands that stabilise these structures are investigated against several diseases, as cancer and viral infections. In turn, G‐quadruplexes can themselves act as therapeutics.

Key Concepts

  • G‐quadruplexes are noncanonical nucleic acid structures that form in guanine‐rich sequences.
  • G‐quadruplexes can form both in the DNA and RNA and are structurally extremely heterogeneous.
  • Both computational and experimental methods have shown the presence of G‐quadruplexes in the genome of humans and other organisms, such as bacteria and viruses.
  • G‐quadruplexes mainly function as epigenetic regulatory elements.
  • G‐quadruplexes interact with a diverse array of cellular proteins, which induce, stabilise or destabilise them.
  • Several methods have been developed to study the G‐quadruplex conformation in short oligonucleotides, longer sequences and whole genomes.
  • Compounds that bind the G‐quadruplex are being studied as inhibitors of important human diseases such as cancer and infective diseases.
  • G‐quadruplex‐folded aptamers have therapeutic potential.

Keywords: G‐rich sequences; noncanonical nucleic acids; tetraplex; nucleic acid structures; folded DNA or RNA

Figure 1. The G‐quadruplex structure. (a) Hoogsteen hydrogen bonds (red dashed lines) between guanine (G) bases make up the G‐quartet. (b) Two or more G‐quartets can stack on top of each other to form the G4. (c) G4s can be formed by four (tetramolecular), two (bimolecular) or one (unimolecular) nucleic acid strands. Source: Edwards, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080664. Licensed under CC by 4.0.
Figure 2. Schematic representation of possible G‐quadruplex conformations. (a) Antiparallel: each strand has adjacent antiparallel neighbours; (b) parallel: four strands oriented in the same direction; (c and d) hybrid 1 and 2: three strands oriented in one direction and the fourth in the opposite direction. The represented structures are those of the human telomeric sequence d[AGGG(TTAGGG)3] in Na+ solution (a), d[AGGG(TTAGGG)3] in a K+‐containing crystal (b), d[TAGGG(TTAGGG)3] in K+ solution with (c) and d[TAGGG(TTAGGG)3TT] in K+ solution (d). G‐rich columns are coloured in black and connecting loops in red; anti and syn guanines in cyan and magenta, respectively. W, M and N denote wide, medium and narrow groove, respectively. Reproduced with permission from Phan et al. . © Oxford University Press.
Figure 3. Schematic illustrating (a) edge‐wise, (b) diagonal, (c) double‐chain reversal or propeller and (d) V‐shaped loops. The loops connect individual strands or columns bridging two G‐tetrad planes. G‐rich columns are coloured in black and connecting loops in red; anti and syn guanines in cyan and magenta, respectively. Reproduced with permission from Patel et al. . © Oxford University Press.
Figure 4. G‐quadruplexes and their regulatory roles in biology. Possible locations of G4s in cells. In the nucleus, G4 formation can occur in double‐stranded G‐rich regions when DNA becomes transiently single‐stranded, during (a) transcription and (c) replication and (b) at the single‐stranded telomeric G‐rich overhangs. Outside the nucleus, G4s can also form in mRNA and (d) are involved in translational control. Red T‐bars indicate impediments to transcription, replication and translation. Reproduced with permission from Rhodes and Lipps, . © Oxford University Press.
Figure 5. Chemical structures of some G4 ligands. BRACO‐19 is an acrydine, TMPyP4 is a porphyrin, PIPER a perylene, c‐ecNDI a naphthalene diimide, PhenDC3 a bisquinolinium derivative and PDS a pyridostatin.
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Further Reading

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Phan AT, Kuryavyi V and Patel DJ (2006) DNA architecture: from G to Z. Current Opinion in Structural Biology 16 (3): 288–298.

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Richter, Sara N(Nov 2018) G‐Quadruplexes (G4s). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028267]