Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding

The extent of thermodynamic stabilization of telomeric G-quadruplex (G4) by isomers of G4 ligand L2H2-6OTD, a telomestatin analog, is inversely correlated with susceptibility to S1 nuclease. L2H2-6OTD facilitated the S1...

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Stabilization of a G-Quadruplex from Unfolding by Replication Protein A Using Potassium and the Porphyrin TMPyP4

Journal of Nucleic Acids ◽

10.4061/2011/529828 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 5

Author(s):

Aishwarya Prakash ◽

Fabien Kieken ◽

Luis A. Marky ◽

Gloria E. O. Borgstahl

Keyword(s):

Dna Replication ◽

Protein A ◽

Thermal Stabilization ◽

Replication Protein A ◽

Replication Protein ◽

Unique Problem ◽

Ssdna Binding ◽

Binding Domains ◽

G Quadruplex ◽

Stabilization Effect

Replication protein A (RPA) plays an essential role in DNA replication by binding and unfolding non-canonical single-stranded DNA (ssDNA) structures. Of the six RPA ssDNA binding domains (labeled A-F), RPA-CDE selectively binds a G-quadruplex forming sequence (5′-TAGGGGAAGGGTTGGAGTGGGTT-3′called Gq23). In K+, Gq23 forms a mixed parallel/antiparallel conformation, and in Na+Gq23 has a less stable (TMlowered by ∼20∘C), antiparallel conformation. Gq23 is intramolecular and 1D NMR confirms a stable G-quadruplex structure in K+. Full-length RPA and RPA-CDE-core can bind and unfold the Na+form of Gq23 very efficiently, but complete unfolding is not observed with the K+form. Studies with G-quadruplex ligands, indicate that TMPyP4 has a thermal stabilization effect on Gq23 in K+, and inhibits complete unfolding by RPA and RPA-CDE-core. Overall these data indicate that G-quadruplexes present a unique problem for RPA to unfold and ligands, such as TMPyP4, could possibly hinder DNA replication by blocking unfolding by RPA.

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Visible-Light Photoswitching of G-Quadruplex Ligand Binding Mode Allows Reversible Control of G-Tetrad Structure

10.26434/chemrxiv.11845272.v2 ◽

2020 ◽

Author(s):

Michael O'Hagan ◽

Javier Ramos Soriano ◽

Susanta Haldar ◽

Juan Carlos Morales ◽

Adrian Mulholland ◽

...

Keyword(s):

Ligand Binding ◽

Visible Light ◽

Uv Light ◽

Binding Mode ◽

High Energy ◽

Light Sources ◽

Biologically Relevant ◽

G Quadruplex ◽

Potential Applications ◽

Robust Regulation

<div><p>Photoresponsive ligands for G-quadruplex oligonucleotides (G4) offer exciting opportunities for the reversible regulation of these assemblies with potential applications in biological chemistry and responsive nanotechnology. However, achieving the robust regulation of G4 ligand activity with low-energy visible light sources that are easily accessible and compatible with biological systems remains a significant challenge to realizing these applications. Herein, we report the G4-binding properties of a photoresponsive dithienylethene (DTE). We demonstrate the first example of G4-specific acceleration of the photoswitching kinetics of a small molecule and the visible-light mediated switching of the G4 ligand binding mode in physiologically-relevant conditions, which in turn allows control over the G4 tetrad structure of telomeric G4 in potassium buffer. The process is fully reversible and avoids the need for high-energy UV light. This affords an efficient, practical and biologically-relevant means of control that may be applied in the generation of new responsive G4/ligand supramolecular systems.</p></div><br>

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Probing G-quadruplex topologies and recognition concurrently in real time and 3D using a dual-app nucleoside probe

Nucleic Acids Research ◽

10.1093/nar/gkz419 ◽

2019 ◽

Vol 47 (12) ◽

pp. 6059-6072 ◽

Cited By ~ 5

Author(s):

Ashok Nuthanakanti ◽

Ishtiyaq Ahmed ◽

Saddam Y Khatik ◽

Kayarat Saikrishnan ◽

Seergazhi G Srivatsan

Keyword(s):

Nucleic Acid ◽

Ligand Binding ◽

Real Time ◽

Telomeric Dna ◽

X Ray ◽

X Ray Crystallography ◽

New Class ◽

Loop Region ◽

Dna Repeat ◽

G Quadruplex

Abstract Comprehensive understanding of structure and recognition properties of regulatory nucleic acid elements in real time and atomic level is highly important to devise efficient therapeutic strategies. Here, we report the establishment of an innovative biophysical platform using a dual-app nucleoside analog, which serves as a common probe to detect and correlate different GQ structures and ligand binding under equilibrium conditions and in 3D by fluorescence and X-ray crystallography techniques. The probe (SedU) is composed of a microenvironment-sensitive fluorophore and an excellent anomalous X-ray scatterer (Se), which is assembled by attaching a selenophene ring at 5-position of 2′-deoxyuridine. SedU incorporated into the loop region of human telomeric DNA repeat fluorescently distinguished subtle differences in GQ topologies and enabled quantify ligand binding to different topologies. Importantly, anomalous X-ray dispersion signal from Se could be used to determine the structure of GQs. As the probe is minimally perturbing, a direct comparison of fluorescence data and crystal structures provided structural insights on how the probe senses different GQ conformations without affecting the native fold. Taken together, our dual-app probe represents a new class of tool that opens up new experimental strategies to concurrently investigate nucleic acid structure and recognition in real time and 3D.

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EXO1 resection at G-quadruplex structures facilitates resolution and replication

Nucleic Acids Research ◽

10.1093/nar/gkaa199 ◽

2020 ◽

Vol 48 (9) ◽

pp. 4960-4975 ◽

Cited By ~ 3

Author(s):

Susanna Stroik ◽

Kevin Kurtz ◽

Kevin Lin ◽

Sergey Karachenets ◽

Chad L Myers ◽

...

Keyword(s):

Dna Replication ◽

Genomic Instability ◽

Secondary Structures ◽

Replication Forks ◽

End Joining ◽

G Quadruplex ◽

Exonuclease 1 ◽

Telomere Loss

Abstract G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.

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DNA Replication through G-Quadruplex Motifs Is Promoted by the Saccharomyces cerevisiae Pif1 DNA Helicase

Cell ◽

10.1016/j.cell.2011.04.015 ◽

2011 ◽

Vol 145 (5) ◽

pp. 678-691 ◽

Cited By ~ 354

Author(s):

Katrin Paeschke ◽

John A. Capra ◽

Virginia A. Zakian

Keyword(s):

Saccharomyces Cerevisiae ◽

Dna Replication ◽

Dna Helicase ◽

G Quadruplex

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Visible-light photoswitching of ligand binding mode suggests G-quadruplex DNA as a target for photopharmacology

Chemical Communications ◽

10.1039/d0cc01581d ◽

2020 ◽

Vol 56 (38) ◽

pp. 5186-5189 ◽

Cited By ~ 1

Author(s):

Michael P. O’Hagan ◽

Javier Ramos-Soriano ◽

Susanta Haldar ◽

Sadiyah Sheikh ◽

Juan C. Morales ◽

...

Keyword(s):

Ligand Binding ◽

Visible Light ◽

Binding Mode ◽

Quadruplex Dna ◽

G Quadruplex

A pyridinium-decorated photoresponsive dithienylethene selectively targets G-quadruplex DNA, allowing binding mode and toxicity to be controlled exclusively with visible light.

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Probing ligand and cation binding sites in G-quadruplex nucleic acids by mass spectrometry and electron photodetachment dissociation sequencing

The Analyst ◽

10.1039/c9an00398c ◽

2019 ◽

Vol 144 (11) ◽

pp. 3518-3524 ◽

Cited By ~ 6

Author(s):

Dababrata Paul ◽

Adrien Marchand ◽

Daniela Verga ◽

Marie-Paule Teulade-Fichou ◽

Sophie Bombard ◽

...

Keyword(s):

Mass Spectrometry ◽

Tandem Mass Spectrometry ◽

Ligand Binding ◽

Binding Sites ◽

Cation Binding ◽

Tandem Mass ◽

Top Down ◽

G Quadruplex ◽

Ligand Binding Sites ◽

Electron Photodetachment

Tandem mass spectrometry: native top-down sequencing by electron photodetachment dissociation (EPD) reveals ligand binding sites on DNA G-quadruplexes.

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Solution NMR Structure of a Ligand/Hybrid-2-G-Quadruplex Complex Reveals Rearrangements that Affect Ligand Binding

Angewandte Chemie ◽

10.1002/ange.201702135 ◽

2017 ◽

Vol 129 (25) ◽

pp. 7208-7212 ◽

Cited By ~ 10

Author(s):

Julia Wirmer-Bartoschek ◽

Lars Erik Bendel ◽

Hendrik R. A. Jonker ◽

J. Tassilo Grün ◽

Francesco Papi ◽

...

Keyword(s):

Ligand Binding ◽

Nmr Structure ◽

Solution Nmr ◽

G Quadruplex

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NovelFeIIandCoIIComplexes of Natural Product Tryptanthrin: Synthesis and Binding with G-Quadruplex DNA

Bioinorganic Chemistry and Applications ◽

10.1155/2016/5075847 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Yi-ning Zhong ◽

Yan Zhang ◽

Yun-qiong Gu ◽

Shi-yun Wu ◽

Wen-ying Shen ◽

...

Keyword(s):

Natural Products ◽

Ligand Binding ◽

Single Crystal ◽

Natural Product ◽

Significant Interaction ◽

Rational Design ◽

X Ray Diffraction ◽

Quadruplex Dna ◽

X Ray ◽

G Quadruplex

Tryptanthrin is one of the most important members of indoloquinoline alkaloids. We obtained this alkaloid fromIsatis. Two novelFeIIandCoIIcomplexes of tryptanthrin were first synthesized. Single-crystal X-ray diffraction analyses show that these complexes display distorted four-coordinated tetrahedron geometry via two heterocyclic nitrogen and oxygen atoms from tryptanthrin ligand. Binding with G-quadruplex DNA properties revealed that both complexes were found to exhibit significant interaction with G-quadruplex DNA. This study may potentially serve as the basis of future rational design of metal-based drugs from natural products that target the G-quadruplex DNA.

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