Evaluation of the effect of polymorphism on G-quadruplex-ligand interaction by means of spectroscopic and chromatographic techniques

Benito, Sonia; Ferrer, Anna; Benabou, Sanae; Aviñó, Anna; Eritja, Ramón; Gargallo, Raimundo

doi:10.1016/j.saa.2018.02.006

Cited by 11 publications

(10 citation statements)

References 48 publications

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“…This modification has a significant effect on the biophysical properties, leading to the stabilization of the parallel-stranded topology. 26,27 The first sequence was used in the present work for CD and fluorescence experiments, the second one for nuclear magnetic resonance (NMR) spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes

Jarošová

Paroulek

Rájecký

et al. 2018

Phys. Chem. Chem. Phys.

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In this work, the interaction of six natural benzo[c]phenanthridine alkaloids (macarpine, sanguilutine, sanguirubine, chelerythrine, sanguinarine and chelirubine) with parallel and antiparallel G-quadruplex DNA structures was studied. HT22 corresponding to the end of human telomeres and the modified promoter oncogene c-kit21 and Pu22 sequences have been used. Spectroscopically-monitored melting experiments and fluorescence titrations, competitive dialysis and nuclear magnetic resonance spectroscopy were used for this purpose. The results showed that these alkaloids stabilized G-quadruplex structures in terms of increments of Tm values (from 15 to 25 °C) with high selectivity over duplexes and unfolded DNA. The mode of binding was mainly by stacking on the terminal G-tetrads with stoichiometries of 1 : 2 (DNA : ligand). The presence of non-specific electrostatic interactions was also observed. Overall, the results pointed to a strong stabilization of G-quadruplex structures by these alkaloids.

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Section: Introductionmentioning

confidence: 99%

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes

Jarošová

Paroulek

Rájecký

et al. 2018

Phys. Chem. Chem. Phys.

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“…However, this did not occur for c-kit21T12T21, which could be indicative of the presence of multimeric structures, other than the monomeric G-quadruplex one [31,32]. This hypothesis is based on a previous work with a similar sequence showing that the residual CD signal was related to the presence of multimeric forms that were stable at this temperature [37]. At this point, size-exclusion chromatography (SEC) measurements provided a complementary insight into the polymorphism of these two sequences [37,38,39].…”

Section: Resultsmentioning

confidence: 99%

“…The injection volume was 15 μL. T 15 , T 20 , T 25 , T 20 and T 45 sequences were used as standards to construct the plot of logarithm of the retention time (t R ) vs. molecular weight [37]. Blue dextran (MW 2,000,000 Da, Sigma-Merck, Darmstadt, Germany) was used as a void volume marker (5.30 mL).…”

Section: Methodsmentioning

confidence: 99%

Stabilization of c-KIT G-Quadruplex DNA Structures by the RNA Polymerase I Inhibitors BMH-21 and BA-41

Mazzini

Gargallo

Musso

et al. 2019

IJMS

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The stabilization of G-quadruplex DNA structures by small molecules with affinity to oncogene promoters has emerged as a promising anticancer strategy, due to a potential role in gene expression regulation. We explored the ability of BMH-21 (1) and its analogue BA-41 (2) to bind the G-quadruplex structure present in the c-KIT promoter by biophysical methods and molecular modeling. We provide evidence that both compounds interact with the c-KIT 21-mer sequence. The stable monomeric intramolecular parallel G-quadruplex obtained by the mutation of positions 12 and 21 allowed the precise determination of the binding mode by NMR and molecular dynamics studies. Both compounds form a complex characterized by one ligand molecule positioned over the tetrad at the 3′-end, stabilized by an extensive network of π–π interactions. The binding constants (Kb) obtained with fluorescence are similar for both complexes (around 106 M−1). Compound BA-41 (2) showed significant antiproliferative activity against a human lymphoma cell line, SU-DHL4, known to express substantial levels of c-KIT. However, the partial inhibition of c-KIT expression by Western blot analysis suggested that the interaction of compound 2 with the c-KIT promoter is not the primary event and that multiple effects provide a contribution as determinants of biological activity.

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“…The stability of these folded structures against changes in temperature were studied by means of melting experiments carried out in presence of KCl. The diluted samples for measurement were prepared following the standard procedure that may be found in many studies studying G-quadruplex structures: the appropriate volumes of buffer and KCl stock solutions were added to an aliquot of the DNA stock solution, the mixture is then heated at 95 °C for 10 minutes and finally cooled overnight inside the heating block 17 .…”

Section: Resultsmentioning

confidence: 99%

“…Previously, the interaction of several G-quadruplex-forming sequences, including the central sequence SMG03, with the crystal violet ligand was studied 17 by means of spectroscopic and separation techniques. From that study it was proposed that the polymorphism of G-quadruplex should be considered in these DNA:ligand interactions.…”

Section: Introductionmentioning

confidence: 99%

A pH-dependent bolt involving cytosine bases located in the lateral loops of antiparallel G-quadruplex structures within the SMARCA4 gene promotor

Benabou

Mazzini

Aviñó

et al. 2019

Sci Rep

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Some lung and ovarian tumors are connected to the loss of expression of SMARCA4 gene. In its promoter region, a 44-nucleotides long guanine sequence prone to form G-quadruplex structures has been studied by means of spectroscopic techniques (circular dichroism, molecular absorption and nuclear magnetic resonance), size exclusion chromatography and multivariate analysis. The results have shown that the central 21-nucleotides long sequence comprising four guanine tracts of disparate length is able to fold into a pH-dependent ensemble of G-quadruplex structures. Based on acid-base titrations and melting experiments of wild and mutated sequences, the formation of a c•c + base pair between cytosine bases present at the two lateral loops is shown to promote a reduction in conformational heterogeneity, as well as an increase in thermal stability. The formation of this base pair is characterized by a pK a value of 7.1 ± 0.2 at 20 °C and 150 mM KCl. This value, higher than those usually found in i-motif structures, is related to the additional stability provided by guanine tetrads in the G-quadruplex. To our knowledge, this is the first thermodynamic description of this base pair in loops of antiparallel G-quadruplex structures. Nucleic acids can adopt structures other than the Watson-Crick double helix, such as the i-motif or G-quadruplex structures with biologically relevant roles. The i-motif is formed within cytosine-rich (C-rich) sequences, being its building block the C•C + base pair. As the protonation of some cytosine bases is needed for its formation, the overall stability of the i-motif structure is strongly dependent on pH 1,2. Because of this fact, the potential role in vivo of i-motif structures is still under investigation 3,4. On the other hand, G-quadruplexes are formed by DNA or RNA sequences that are particularly rich in guanine bases. The building block of these structures is the G-quartet (or G-tetrad), which consist on four guanine bases held together by Hoogsteen-type hydrogen bonds in a planar arrangement (Fig. 1a). G-quadruplex structures are mainly stabilized by intramolecular or intermolecular stacking of these G-quartets, as well as by electrostatic interactions with cations (such as K + or Na +) placed within the structure. G-quadruplex structure variability depends strongly on the length of the guanine tracks, the loops connecting the stacked G-quartets, the syn/anti preference of the purine bases, and the presence of ligands or modifiers. Hence, G-quadruplexes may be classified into 'antiparallel' , 'parallel' or even 'hybrid' arrangements (Fig. 1b) 5. The in vitro formation of such structures in DNA sequences corresponding to the end of telomeres and to the promoter regions of several oncogenes has previously been shown, as well as their in vivo presence 6,7. Hence, the role of G-quadruplex structures in biological processes like cancer or aging seems to be clear 8-12. Accordingly, research is being made to identify ligands that could selectively bind to G-quadruplex structures to modulate g...

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Evaluation of the effect of polymorphism on G-quadruplex-ligand interaction by means of spectroscopic and chromatographic techniques

Cited by 11 publications

References 48 publications

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes

Naturally occurring quaternary benzo[c]phenanthridine alkaloids selectively stabilize G-quadruplexes

Stabilization of c-KIT G-Quadruplex DNA Structures by the RNA Polymerase I Inhibitors BMH-21 and BA-41

A pH-dependent bolt involving cytosine bases located in the lateral loops of antiparallel G-quadruplex structures within the SMARCA4 gene promotor

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