Coexistence of two quadruplex–duplex hybrids in the PIM1 gene

Tan, D.; Winnerdy, Fernaldo Richtia; Lim, Kah Wai; Phan, Anh Tuân

doi:10.1093/nar/gkaa752

Cited by 25 publications

(34 citation statements)

References 85 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[1,2] In fact, several natural and designed quadruplex-forming sequences fold to feature Q-D interfaces by having loops, bulges, or flanking sequences able to selfassociate into a duplex hairpin. [3][4][5][6] Upon the engineering of quadruplex scaffolds, duplex extensions in quadruplexes were shown to promote quadruplex folding or to drive folding into defined quadruplex topologies. [7][8][9][10] Also, RNA Q-D junctions were reported to be specifically recognized by the human fragile X mental retardation RGG peptide [11,12] and anti-thrombotic quadruplexes featuring Q-D interfaces have demonstrated their great potency as biomedical aptamers.…”

Section: Introductionmentioning

confidence: 99%

“…It has been pointed out that quadruplex formation in the genome may entail the presence of Q‐D junctions through the Watson‐Crick pairing within an appropriate loop element or between a flanking sequence with the single‐stranded complementary strand [1,2] . In fact, several natural and designed quadruplex‐forming sequences fold to feature Q‐D interfaces by having loops, bulges, or flanking sequences able to self‐associate into a duplex hairpin [3–6] . Upon the engineering of quadruplex scaffolds, duplex extensions in quadruplexes were shown to promote quadruplex folding or to drive folding into defined quadruplex topologies [7–10] .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

Vianney

Weisz

2022

Chemistry A European J

View full text Add to dashboard Cite

Quadruplex-duplex (Q-D) junctions are increasingly considered promising targets for medicinal and technological applications. Here, a Q-D hybrid with a hairpin-type snapback loop coaxially stacked onto the quadruplex 3'-outer tetrad was designed and employed as a target structure for the indoloquinoline ligand SYUIQ-5. NMR spectral analysis demonstrated high-affinity binding of the ligand at the quadruplex-duplex interface with association constants determined by isothermal titration calorimetry of about 10 7 M À 1 and large exothermicities ΔH°of À 14 kcal/mol in a 120 mM K + buffer at 40 °C. Determination of the ligand-bound hybrid structure revealed intercalation of SYUIQ-5 between 3'-outer tetrad and the neighboring CG base pair, maximizing π-π stacking as well as electrostatic interactions with guanine carbonyl groups in close vicinity to the positively charged protonated quinoline nitrogen of the tetracyclic indoloquinoline. Exhibiting considerable flexibility, the SYUIQ-5 sidechain resides in the duplex minor groove. Based on comparative binding studies with the non-substituted N5-methylated indoloquinoline cryptolepine, the sidechain is suggested to confer additional affinity and to fix the alignment of the intercalated indoloquinoline aromatic core. However, selectivity for the Q-D junction mostly relies on the geometry and charge distribution of the indoloquinoline ring system. The presented results are expected to provide valuable guidelines for the design of ligands specifically targeting Q-D interfaces.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

Vianney

Weisz

2022

Chemistry A European J

View full text Add to dashboard Cite

show abstract

“…The first TCTGA lateral loop stacks coaxially onto the G-core with several NOE cross-peaks connecting T3/A7 residues with imino protons of the adjacent G-tetrad (Figure C and Figure S10A,C). Given a loop bridging a wide groove, an interfacial Watson–Crick AT base pair should easily be accommodated. − However, there is an unusual Hoogsteen-type base pairing alignment between T3 and A7 in all calculated structures (Figure B).…”

Section: Resultsmentioning

confidence: 99%

First Tandem Repeat of a Potassium Channel KCNN4 Minisatellite Folds into a V-Loop G-Quadruplex Structure

Vianney

Weisz

2021

Biochemistry

View full text Add to dashboard Cite

The KCNN4 gene encoding a potassium channel protein whose expression has been correlated with tumor progression was found to comprise a guanine-rich minisatellite region with the ability to form a putative G-quadruplex (G4). Given the suggested regulatory role of G4s in gene expression, Gquadruplex formation for the polymorphic first repeat of the minisatellite was studied by nuclear magnetic resonance spectroscopy. A stable G-quadruplex of a truncated mutant sequence was shown to represent one of several coexisting species of the wild-type sequence. The high-resolution structure features a noncanonical G4 with a broken G-column and a V-shaped loop. The presence of a 3′-flanking thymidine interacting with the lateral loop preceding the V loop seems to be critical for the formation of this G4 topology. On the contrary, an additional 5′-flanking residue disfavored but still allowed folding into the V-loop structure. The latter may therefore serve as a putative therapeutic target in strategies for G4based modulation of KCNN4 expression.

show abstract

“…More than 80,000 DNA sequences capable of folding into QDH structures with stem-loops of 20 nucleotides or less have been identified across important regulatory sites in the human genome, including transcription/mutagenesis hotspots and cancer-associated genes [19]. The folding topologies of various QDH structures have been characterized in vitro by NMR [19][20][21][22]. The stem-loop in QDH may be positioned in a coaxial or orthogonal orientation relative to the G-quadruplex core, and the topology of the core is sensitive to the orientation of the loop [17].…”

Section: Introductionmentioning

confidence: 99%

Stabilization of G-Quadruplex-Duplex Hybrid Structures Induced by Minor Groove-Binding Drugs

Scott

Chalikian

2022

Life

View full text Add to dashboard Cite

Once it had been realized that G-quadruplexes exist in the cell and are involved in regulation of genomic processes, the quest for ligands recognizing these noncanonical structures was underway. Many organic compounds that tightly associate with G-quadruplexes have been identified. However, the specificity of G-quadruplex-binding ligands towards individual structures remains problematic, as the common recognition element of these ligands is the G-tetrad. In this paper, we focus on G-quadruplex-duplex hybrids (QDH) containing a hairpin duplex incorporated as a stem-loop into the G-quadruplex core. The presence of a stem-loop renders QDH amenable to sequence-specific recognition by duplex-binding drugs. Should the thermodynamic crosstalk between the stem-loop and the tetraplex core be sufficiently strong, the drug binding to the loop would lead to the stabilization of the entire structure. We studied the stabilizing influence of the minor groove-binders netropsin and Hoechst 33258 on a family of QDH structures, as well as a G-quadruplex and a hairpin modeling the G-quadruplex core and the stem-loop of the QDH’s. We found that the binding of either drug results in an enhancement of the thermal stability of all DNA structures, as expressed by increases in the melting temperature, TM. Analysis of the hierarchical order of increases in TM revealed that the drug-induced stabilization arises from drug binding to the G-quadruplex domain of a QDH and the stem-loop, if the latter contains an all-AT binding site. This result attests to the thermodynamic crosstalk between the stem-loop and the tetraplex core of a QDH. Given the existing library of minor groove-binding drugs recognizing mixed A·T and G·C DNA sequences, our results point to an untapped avenue for sequence-specific recognition of QDH structures in vitro and, possibly, in vivo; thereby, opening the way for selective stabilization of four-stranded DNA structures at predetermined genomic loci, with implications for the control of genomic events.

show abstract

Coexistence of two quadruplex–duplex hybrids in the PIM1 gene

Cited by 25 publications

References 85 publications

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

First Tandem Repeat of a Potassium Channel KCNN4 Minisatellite Folds into a V-Loop G-Quadruplex Structure

Stabilization of G-Quadruplex-Duplex Hybrid Structures Induced by Minor Groove-Binding Drugs

Contact Info

Product

Resources

About