DNA G-quadruplex and its potential as anticancer drug target

Onel, Buket; Lin, Clement; Yang, Danzhou

doi:10.1007/s11426-014-5235-3

Cited by 61 publications

(55 citation statements)

References 89 publications

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“…31 It is intriguing that the P1G4 G-quadruplex appears to be a dynamic equilibrium of two parallel structures, one broken-strand, both with a novel hairpin conformation adopted by the middle loop. DNA quadruplexes with duplex motifs have been shown to be quite tolerable.…”

Section: Discussionmentioning

confidence: 99%

A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription

et al. 2016

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The abnormal over-expression of the BCL2 gene is associated with many human tumors. We found a new 28-mer G-quadruplex-forming sequence, P1G4, immediately upstream of the human BCL2 gene P1 promoter. The P1G4 is shown to be a transcription repressor using a promoter-driven luciferase assay; its inhibitory effect can be markedly enhanced by the G-quadruplex-interactive compound TMPyP4. G-quadruplex can readily form in the P1G4 sequence under physiological salt condition as shown by DMS footprinting. P1G4 and previously identified Pu39 G-quadruplexes appear to form independently in adjacent regions in the BCL2 P1 promoter. In the extended BCL2 P1 promoter region containing both Pu39 and P1G4, P1G4 appears to play a more dominant role in repressing the transcriptional activity. Using NMR spectroscopy, the P1G4 G-quadruplex appears to be a novel dynamic equilibrium of two parallel structures, one regular with two 1-nt loops and a 12-nt middle loop and another broken-strand with three 1-nt loops and a 11-nt middle loop; both structures adopt a novel hairpin (stem-loop duplex) conformation in the long loop. The dynamic equilibrium of two closely related structures and the unique hairpin loop conformation are specific to the P1G4 sequence and distinguish the P1G4 quadruplex from other parallel structures. The presence of P1G4 and Pu39 in adjacent regions of the BCL2 P1 promoter suggests a mechanism for precise regulation of BCL2 gene transcription. The unique P1G4 G-quadruplex may provide a specific target for small molecules to modulate BCL2 gene transcription.

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Section: Discussionmentioning

confidence: 99%

A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription

et al. 2016

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“…Intramolecular G-quadruplexes are of intensive research interest currently due to their potential formation in single-stranded telomeres and oncogene promoter regions [1, 4–7]. Intramolecular G-quadruplex structures form quickly in solution and are found to be DNA sequence-specific, exhibiting great conformational diversity, such as in folding topologies, loop conformations, and capping structures [1].…”

Section: Introductionmentioning

confidence: 99%

“…Targeting of DNA G-quadruplex secondary structures represents a new approach for cancer therapeutics [1, 7, 38–40], with the first report of targeting G-quadruplexes for inhibiting telomerase activity in 1997 [41]. Formation of diverse G-quadruplex structures offers an opportunity to design small molecules/ligands that can selectively bind different G-quadruplexes.…”

Section: Introductionmentioning

confidence: 99%

Human Telomeric G-Quadruplex Structures and G-Quadruplex-Interactive Compounds

Lin

Yang

2017

Methods in Molecular Biology

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G-quadruplexes are noncanonical secondary structures formed in DNA sequences containing consecutive runs of guanines. It has been shown that the 3′ G-rich single-stranded overhangs of human telomeres can form G-quadruplex structures, and the human telomeric DNA G-quadruplexes are considered attractive targets for anticancer drugs. G-quadruplex-interactive compounds have been shown to inhibit telomerase access as well as telomere capping. Nuclear magnetic resonance (NMR) spectroscopy is a powerful method in determining the G-quadruplex structures under physiologically relevant conditions. We present the NMR and biophysical methodology used in our research group for the study of G-quadruplex structures in physiologically relevant solution and their interactions with small-molecule compounds.

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“…21−27 This approach has been used to target c-myc expression in cancer. 28−30 Gquadruplex sequences have also been found in the untranslated regions (UTRs) and coding regions of RNA where they can regulate translation and other cellular processes. 31−36 Quadruplex formation can be monitored via various spectroscopic techniques, including circular dichroism (CD), UV−vis absorption, and nuclear magnetic resonance (NMR) spectroscopies.…”

Section: ■ Introductionmentioning

confidence: 99%

Steady-State and Time-Resolved Studies into the Origin of the Intrinsic Fluorescence of G-Quadruplexes

et al. 2016

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Stretches of guanines in DNA and RNA can fold into guanine quadruplex structures (GQSs). These structures protect telomeres in DNA and regulate gene expression in RNA. GQSs have an intrinsic fluorescence that is sensitive to different parameters, including loop sequence and length. However, the dependence of GQS fluorescence on solution and sequence parameters and the origin of this fluorescence are poorly understood. Herein we examine effects of dangling nucleotides and cosolute conditions on GQS fluorescence using both steady-state and time-resolved fluorescence spectroscopy. The quantum yield of dGGGTGGGTGGGTGGG, termed "dG3T", is found to be modest at ∼2 × 10(-3). Nevertheless, dG3T and its variants are significantly brighter than the common nucleic acid fluorophore 2-aminopurine (2AP) largely due to their sizable extinction coefficients. Dangling 5'-end nucleotides generally reduce emission and blue-shift the resultant spectrum, whereas dangling 3'-end nucleotides slightly enhance fluorescence, particularly on the red side of the emission band. Time-resolved fluorescence decays are broadly distributed in time and require three exponential components for accurate fits. Time-resolved emission spectra suggest the presence of two emitting populations centered at ∼330 and ∼390 nm, with the redder component being a well-defined long-lived (∼1 ns) entity. Insights into GQS fluorescence obtained here should be useful in designing brighter intrinsic RNA and DNA quadruplexes for use in label-free biotechnological applications.

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DNA G-quadruplex and its potential as anticancer drug target

Cited by 61 publications

References 89 publications

A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription

A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription

Human Telomeric G-Quadruplex Structures and G-Quadruplex-Interactive Compounds

Steady-State and Time-Resolved Studies into the Origin of the Intrinsic Fluorescence of G-Quadruplexes

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