Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?

Balasubramanian, Shankar; Hurley, Laurence H.; Neidle, Stephen

doi:10.1038/nrd3428

Cited by 1,541 publications

(1,494 citation statements)

References 137 publications

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“…75 Since MYC is an oncogene with a G-quadruplex structure in the promoter region, 34,76 it was important to determine whether GTC365 effects the repression of hTERT promoter activity directly by binding to the hTERT promoter G-quadruplex or by indirectly modulating MYC transcription through the MYC promoter G-quadruplex. To distinguish between these possibilities, two constructs were prepared, the first being the pGL3-WT plasmid encoding luciferase as a reporter gene and contains the 360 base-pair hTERT promoter region including the upstream E-box (CACGTG) and the core region, and the second (pGL3-E-box mutant) being the same plasmid but with a E-box mutation (TTTGTG.…”

Section: Gtc365 Work Directly Through the Htert Promoter To Lower Htmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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Activation of human telomerase reverse transcriptase (hTERT) is necessary for limitless replication in tumorigenesis. Whereas hTERT is transcriptionally silenced in normal cells, most tumor cells reactivate hTERT expression by alleviating transcriptional repression through diverse genetic and epigenetic mechanisms. Transcription-activating hTERT promoter mutations have been found to occur at high frequencies in multiple cancer types. These mutations have been shown to form new transcription factor binding sites that drive hTERT expression, but this model cannot fully account for differences in wildtype (WT) and mutant promoter activation and has not yet enabled a selective therapeutic strategy. Here we demonstrate a novel mechanism by which promoter mutations activate hTERT transcription, which also sheds light on a unique therapeutic opportunity. Promoter mutations occur in a core promoter region that forms tertiary structures consisting of a pair of G-quadruplexes involved in transcriptional silencing.We show that promoter mutations exert a detrimental effect on the folding of one of these Gquadruplexes, resulting in a nonfunctional silencer element that alleviates transcriptional repression. We have also identified a small drug-like pharmacological chaperone (pharmacoperone) molecule, GTC365, that acts at an early step in the G-quadruplex folding pathway to redirect mutant promoter G-quadruplex misfolding, partially reinstate the correct folding pathway, and reduce hTERT activity through transcriptional repression. This transcription-mediated repression effects cancer cell death through multiple routes including both induction of apoptosis through inhibition of hTERT's role in regulating apoptosis-related proteins and inducing senescence by decreasing telomerase activity and telomere length.We demonstrate the selective therapeutic potential of this strategy in melanoma cells that overexpress hTERT.3

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Section: Gtc365 Work Directly Through the Htert Promoter To Lower Htmentioning

confidence: 99%

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

et al. 2016

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“…Recent biochemical investigations indicate that these G‐rich sequences play crucial roles in cellular processes, such as chromosome maintenance, as well as transcriptional and translational regulation of several protooncogenes, which have been found to be in consensus with the ability of these sequences to form stable GQ structures in vitro 5, 6. Consequently, stabilization of GQ structures by small‐molecule ligands has emerged as a novel approach to cancer therapeutics 7. In this context, several small‐molecule ligands that bind and stabilize GQs are being rigorously evaluated as chemotherapeutic candidates, and have been used as tools to understand the biological role of GQ‐forming sequences 8, 9…”

Section: Introductionmentioning

confidence: 99%

Probing Human Telomeric DNA and RNA Topology and Ligand Binding in a Cellular Model by Using Responsive Fluorescent Nucleoside Probes

et al. 2017

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The development of biophysical systems that enable an understanding of the structure and ligand‐binding properties of G‐quadruplex (GQ)‐forming nucleic acid sequences in cells or models that mimic the cellular environment would be highly beneficial in advancing GQ‐directed therapeutic strategies. Herein, the establishment of a biophysical platform to investigate the structure and recognition properties of human telomeric (H‐Telo) DNA and RNA repeats in a cell‐like confined environment by using conformation‐sensitive fluorescent nucleoside probes and a widely used cellular model, bis(2‐ethylhexyl) sodium sulfosuccinate reverse micelles (RMs), is described. The 2′‐deoxy and ribonucleoside probes, composed of a 5‐benzofuran uracil base analogue, faithfully report the aqueous micellar core through changes in their fluorescence properties. The nucleoside probes incorporated into different loops of H‐Telo DNA and RNA oligonucleotide repeats are minimally perturbing and photophysically signal the formation of respective GQ structures in both aqueous buffer and RMs. Furthermore, these sensors enable a direct comparison of the binding affinity of a ligand to H‐Telo DNA and RNA GQ structures in the bulk and confined environment of RMs. These results demonstrate that this combination of a GQ nucleoside probe and easy‐to‐handle RMs could provide new opportunities to study and devise screening‐compatible assays in a cell‐like environment to discover GQ binders of clinical potential.

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“…The biophysical characterization of G quadruplexes has received much attention due to the potential to design new therapies based on the specific molecular recognition of the DNA quadruplexes by small molecules [40][41][42][43][44]. As we, and others, have described earlier, the solution structures of DNA quadruplexes are very sensitive to changes in DNA sequence context as well as to changes in solution environment.…”

Section: Introductionmentioning

confidence: 99%

The Human Telomere Sequence, (TTAGGG)4, in the Absence and Presence of Cosolutes: A Spectroscopic Investigation

Sharma

Sheardy

2014

Molecules

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Abstract:Historically, biophysical studies of nucleic acids have been carried out under near ideal conditions, i.e., low buffer concentration (e.g., 10 mM phosphate), pH 7, low ionic strength (e.g., 100 mM) and, for optical studies, low concentrations of DNA (e.g., 1 × 10 −6 M). Although valuable structural and thermodynamic data have come out of these studies, the conditions, for the most, part, are inadequate to simulate realistic cellular conditions. The increasing interest in studying biomolecules under more cellular-like conditions prompted us to investigate the effect of osmotic stress on the structural and thermodynamic properties of DNA oligomers containing the human telomere sequence (TTAGGG). Here, we report the characterization of (TTAGGG) 4 in potassium phosphate buffer with increasing percent PEG (polyethylene glycol) or acetonitrile. In general, the presence of these cosolutes induces a conformational change from a unimolecular hybrid structure to a multimolecular parallel stranded structure. Hence, the structural change is accompanied with a change in the molecularity of quadruplex formation.

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Targeting G-quadruplexes in gene promoters: a novel anticancer strategy?

Cited by 1,541 publications

References 137 publications

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

A Pharmacological Chaperone Molecule Induces Cancer Cell Death by Restoring Tertiary DNA Structures in Mutant hTERT Promoters

Probing Human Telomeric DNA and RNA Topology and Ligand Binding in a Cellular Model by Using Responsive Fluorescent Nucleoside Probes

The Human Telomere Sequence, (TTAGGG)4, in the Absence and Presence of Cosolutes: A Spectroscopic Investigation

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