Impact of Small Molecules on Intermolecular G-Quadruplex Formation

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2019 Apr 24

PMID 31010019

Citations 2

Authors

Prabesh Gyawali

Keshav Gc

Yue Ma

Sanjaya Abeysirigunawardena

Kazuo Nagasawa

Hamza Balci

Affiliations

Soon will be listed here.

Abstract

We performed single molecule studies to investigate the impact of several prominent small molecules (the oxazole telomestatin derivative L2H2-6OTD, pyridostatin, and Phen-DC) on intermolecular G-quadruplex (i-GQ) formation between two guanine-rich DNA strands that had 3-GGG repeats in one strand and 1-GGG repeat in the other (3+1 GGG), or 2-GGG repeats in each strand (2+2 GGG). Such structures are not only physiologically significant but have recently found use in various biotechnology applications, ranging from DNA-based wires to chemical sensors. Understanding the extent of stability imparted by small molecules on i-GQ structures, has implications for these applications. The small molecules resulted in different levels of enhancement in i-GQ formation, depending on the small molecule and arrangement of GGG repeats. The largest enhancement we observed was in the 3+1 GGG arrangement, where i-GQ formation increased by an order of magnitude, in the presence of L2H2-6OTD. On the other hand, the enhancement was limited to three-fold with Pyridostatin (PDS) or less for the other small molecules in the 2+2 GGG repeat case. By demonstrating detection of i-GQ formation at the single molecule level, our studies illustrate the feasibility to develop more sensitive sensors that could operate with limited quantities of materials.

Citing Articles

Fast interaction dynamics of G-quadruplex and RGG-rich peptides unveiled in zero-mode waveguides.

Patra S, Claude J, Naubron J, Wenger J Nucleic Acids Res. 2021; 49(21):12348-12357.

PMID: 34791437 PMC: 8643622. DOI: 10.1093/nar/gkab1002.

Quantifying the impact of small molecule ligands on G-quadruplex stability against Bloom helicase.

Maleki P, Mustafa G, Gyawali P, Budhathoki J, Ma Y, Nagasawa K Nucleic Acids Res. 2019; 47(20):10744-10753.

PMID: 31544934 PMC: 6847008. DOI: 10.1093/nar/gkz803.

References

Merkina E, Fox K . Kinetic stability of intermolecular DNA quadruplexes. Biophys J. 2005; 89(1):365-73. PMC: 1366536. DOI: 10.1529/biophysj.105.061259. View

Fernando H, Reszka A, Huppert J, Ladame S, Rankin S, Venkitaraman A . A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene. Biochemistry. 2006; 45(25):7854-60. PMC: 2195898. DOI: 10.1021/bi0601510. View

De Cian A, Delemos E, Mergny J, Teulade-Fichou M, Monchaud D . Highly efficient G-quadruplex recognition by bisquinolinium compounds. J Am Chem Soc. 2007; 129(7):1856-7. DOI: 10.1021/ja067352b. View

Rodriguez R, Muller S, Yeoman J, Trentesaux C, Riou J, Balasubramanian S . A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres. J Am Chem Soc. 2008; 130(47):15758-9. PMC: 2746963. DOI: 10.1021/ja805615w. View

Fernando H, Sewitz S, Darot J, Tavare S, Huppert J, Balasubramanian S . Genome-wide analysis of a G-quadruplex-specific single-chain antibody that regulates gene expression. Nucleic Acids Res. 2009; 37(20):6716-22. PMC: 2777450. DOI: 10.1093/nar/gkp740. View

Iida K, Tera M, Hirokawa T, Shin-Ya K, Nagasawa K . G-quadruplex recognition by macrocyclic hexaoxazole (6OTD) dimer: greater selectivity than monomer. Chem Commun (Camb). 2009; (42):6481-3. DOI: 10.1039/b910242f. View

Morris M, Negishi Y, Pazsint C, Schonhoft J, Basu S . An RNA G-quadruplex is essential for cap-independent translation initiation in human VEGF IRES. J Am Chem Soc. 2010; 132(50):17831-9. DOI: 10.1021/ja106287x. View

Freeman R, Liu X, Willner I . Chemiluminescent and chemiluminescence resonance energy transfer (CRET) detection of DNA, metal ions, and aptamer-substrate complexes using hemin/G-quadruplexes and CdSe/ZnS quantum dots. J Am Chem Soc. 2011; 133(30):11597-604. DOI: 10.1021/ja202639m. View

Sen D, Poon L . RNA and DNA complexes with hemin [Fe(III) heme] are efficient peroxidases and peroxygenases: how do they do it and what does it mean?. Crit Rev Biochem Mol Biol. 2011; 46(6):478-92. DOI: 10.3109/10409238.2011.618220. View

10.

Kosman J, Juskowiak B . Peroxidase-mimicking DNAzymes for biosensing applications: a review. Anal Chim Acta. 2011; 707(1-2):7-17. DOI: 10.1016/j.aca.2011.08.050. View

11.

Shimron S, Wang F, Orbach R, Willner I . Amplified detection of DNA through the enzyme-free autonomous assembly of hemin/G-quadruplex DNAzyme nanowires. Anal Chem. 2012; 84(2):1042-8. DOI: 10.1021/ac202643y. View

12.

Rahman K, Tizkova K, Reszka A, Neidle S, Thurston D . Identification of novel telomeric G-quadruplex-targeting chemical scaffolds through screening of three NCI libraries. Bioorg Med Chem Lett. 2012; 22(8):3006-10. DOI: 10.1016/j.bmcl.2012.02.020. View

13.

He H, Chan D, Leung C, Ma D . A highly selective G-quadruplex-based luminescent switch-on probe for the detection of gene deletion. Chem Commun (Camb). 2012; 48(76):9462-4. DOI: 10.1039/c2cc32253f. View

14.

Largy E, Granzhan A, Hamon F, Verga D, Teulade-Fichou M . Visualizing the quadruplex: from fluorescent ligands to light-up probes. Top Curr Chem. 2012; 330:111-77. DOI: 10.1007/128_2012_346. View

15.

Zhou H, Wu Z, Shen G, Yu R . Intermolecular G-quadruplex structure-based fluorescent DNA detection system. Biosens Bioelectron. 2012; 41:262-7. DOI: 10.1016/j.bios.2012.08.028. View

16.

Mitchell T, Ramos-Montoya A, Di Antonio M, Murat P, Ohnmacht S, Micco M . Downregulation of androgen receptor transcription by promoter g-quadruplex stabilization as a potential alternative treatment for castrate-resistant prostate cancer. Biochemistry. 2013; 52(8):1429-36. DOI: 10.1021/bi301349c. View

17.

Iida K, Majima S, Nakamura T, Seimiya H, Nagasawa K . Evaluation of the interaction between long telomeric DNA and macrocyclic hexaoxazole (6OTD) dimer of a G-quadruplex ligand. Molecules. 2013; 18(4):4328-41. PMC: 6269967. DOI: 10.3390/molecules18044328. View

18.

McLuckie K, Di Antonio M, Zecchini H, Xian J, Caldas C, Krippendorff B . G-quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells. J Am Chem Soc. 2013; 135(26):9640-3. PMC: 3964824. DOI: 10.1021/ja404868t. View

19.

Rajendran A, Endo M, Hidaka K, Tran P, Mergny J, Sugiyama H . Controlling the stoichiometry and strand polarity of a tetramolecular G-quadruplex structure by using a DNA origami frame. Nucleic Acids Res. 2013; 41(18):8738-47. PMC: 3794576. DOI: 10.1093/nar/gkt592. View

20.

Iida K, Nakamura T, Yoshida W, Tera M, Nakabayashi K, Hata K . Fluorescent-ligand-mediated screening of G-quadruplex structures using a DNA microarray. Angew Chem Int Ed Engl. 2013; 52(46):12052-5. DOI: 10.1002/anie.201305366. View