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15. G-quadruplex

Author

Monsen, Robert C., Trent, John O., and Chaires, Jonathan B.

Abstract

G-quadruplexes (G4s) are distinctive four-stranded DNA or RNA structures found within cells that are thought to play functional roles in gene regulation and transcription, translation, recombination, and DNA damage/repair. While G4 structures can be uni-, bi-, or tetramolecular with respect to strands, folded unimolecular conformations are most significant in vivo. Unimolecular G4 can potentially form in sequences with runs of guanines interspersed with what will become loops in the folded structure: 5′GxLyGxLyGxLyGx, where xis typically 2–4 and yis highly variable. Such sequences are highly conserved and specifically located in genomes. In the folded structure, guanines from each run combine to form planar tetrads with four hydrogen-bonded guanine bases; these tetrads stack on one another to produce four strand segments aligned in specific parallel or antiparallel orientations, connected by the loop sequences. Three types of loops (lateral, diagonal, or “propeller”) have been identified. The stacked tetrads form a central cavity that features strong coordination sites for monovalent cations that stabilize the G4 structure, with potassium or sodium preferred. A single monomeric G4 typically forms from a sequence containing roughly 20–30 nucleotides. Such short sequences have been the primary focus of X-ray crystallographic or NMR studies that have produced high-resolution structures of a variety of monomeric G4 conformations. These structures are often used as the basis for drug design efforts to modulate G4 function.

Published
2022
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16. Early Events in G-quadruplex Folding Captured by Time-Resolved Small-Angle X-Ray Scattering.

Author

Monsen RC, Sabo TM, Gray R, Hopkins JB, and Chaires JB

Abstract

Time-resolved small-angle X-ray experiments (TR-SAXS) are reported here that capture and quantify a previously unknown rapid collapse of the unfolded oligonucleotide as an early step in G4 folding of hybrid 1 and hybrid 2 telomeric G-quadruplex structures. The rapid collapse, initiated by a pH jump, is characterized by an exponential decrease in the radius of gyration from 20.6 to 12.6 Å. The collapse is monophasic and is complete in less than 600 ms. Additional hand-mixing pH-jump kinetic studies show that slower kinetic steps follow the collapse. The folded and unfolded states at equilibrium were further characterized by SAXS studies and other biophysical tools, to show that G4 unfolding was complete at alkaline pH, but not in LiCl solution as is often claimed. The SAXS Ensemble Optimization Method (EOM) analysis reveals models of the unfolded state as a dynamic ensemble of flexible oligonucleotide chains with a variety of transient hairpin structures. These results suggest a G4 folding pathway in which a rapid collapse, analogous to molten globule formation seen in proteins, is followed by a confined conformational search within the collapsed particle to form the native contacts ultimately found in the stable folded form.

Published
2024
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17. Putting a New Spin of G-Quadruplex Structure and Binding by Analytical Ultracentrifugation.

Author

Dean WL, Gray RD, DeLeeuw L, Monsen RC, and Chaires JB

Subjects
Molecular Weight, Structure-Activity Relationship, G-Quadruplexes, Ultracentrifugation methods
Abstract

Analytical ultracentrifugation is a powerful biophysical tool that provides information about G-quadruplex structure, stability, and binding reactivity. This chapter provides a simplified explanation of the method, along with examples of how it can be used to characterize G4 formation and to monitor small-molecule binding.

Published
2019
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