scholarly journals Studies on the Interactions of 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium and Insulin with the Quadruplex-Forming Oligonucleotide Sequence a2 from the Insulin-Linked Polymorphic Region

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6595
Author(s):  
Peter Jonas Wickhorst ◽  
Heiko Ihmels ◽  
Thomas Paululat
Keyword(s):  
Biological Activity ◽  
Promoter Region ◽  
Spectroscopic Studies ◽  
Polymorphic Region ◽  
Quadruplex Dna ◽  
Preferential Formation ◽  
High Affinity ◽  
Quadruplex Structure ◽  
G4 Dna ◽  
Oligonucleotide Sequence

Recently, several quadruplex-DNA-forming sequences have been identified in the insulin-linked polymorphic region (ILPR), which is a guanine-rich oligonucleotide sequence in the promoter region of insulin. The formation of this non-canonical quadruplex DNA (G4-DNA) has been shown to be involved in the biological activity of the ILPR, specifically with regard to its interplay with insulin. In this context, this contribution reports on the investigation of the association of the quadruplex-forming ILPR sequence a2 with insulin as well as with the well-known G4-DNA ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium (1), also named RHPS4, by optical and NMR spectroscopy. CD- and NMR-spectroscopic measurements confirmed the preferential formation of an antiparallel quadruplex structure of a2 with four stacked guanine quartets. Furthermore, ligand 1 has high affinity toward a2 and binds by terminal π stacking to the G1–G11–G15–G25 quartet. In addition, the spectroscopic studies pointed to an association of insulin to the deoxyribose backbone of the loops of a2.

Spectroscopic Studies on the Binding Properties of Ofloxacin and Human Telomeric G-Quadruplex DNA

2013 ◽  
Vol 634-638 ◽  
pp. 1062-1065 ◽  
Author(s):  
Xu Jian Luo ◽  
Qi Pin Qin ◽  
Yu Lan Li ◽  
Yan Yang
Keyword(s):  
Spectral Analysis ◽  
Fluorescence Emission ◽  
Spectroscopic Studies ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
G Quadruplex ◽  
Shoulder Peak ◽  
Binding Intensity ◽  
Dna Complex

The binding of ofloxacin with human telomeric G-quadruplex DNA, Htel-G4-DNA and Htel-3-G4-DNA were examined by Fluorescence and CD spectroscopic methods. In the Fluorescence emission spectral analysis, the addition of ofloxacin induced significant quenching on the fluorescence emission of TO-G4-DNA complex. The fluorescence spectral analysis indicated that ofloxacin exhibited higher binding affinity and binding intensity to Htel-G4-DNA than Htel-3-G4-DNA. In the CD spectral analysis, the interaction with ofloxacin did not disturb the characteristic absorption of Htel-G4-DNA at 290 nm corresponding to its antiparallel form, and only slightly increased the positive absorption at 270 nm as shoulder peak, which suggests the antiparallel structure of G-quadruplex can remain stable in the presence of ofloxacin

scholarly journals Effect of Ionic Strength on Porphyrin Drugs Interaction with Quadruplex DNA Formed by the Promoter Region of C-myc and Bcl2 Oncogenes

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Narayana Nagesh ◽  
Varun K. Sharma ◽  
A. Ganesh Kumar ◽  
Edwin A. Lewis
Keyword(s):  
Ionic Strength ◽  
Fluorescence Spectroscopy ◽  
Drug Interactions ◽  
Promoter Region ◽  
Promoter Regions ◽  
Quadruplex Dna ◽  
Quadruplex Structure ◽  
G Quadruplex ◽  
Drugs Interaction ◽  
Dna Complex

C-myc and Bcl2 are well characterized oncogenes that are capable of forming G-quadruplex structures. Promoter regions of C-myc and Bcl2 forming G-quadruplex structures are chemically synthesized and G-quadruplex structure is formed in presence of 100 mM potassium ion. Three different porphyrin drugs, namely TMPyP2, TMPyP3, and TMPyP4 are allowed to interact with quadruplex DNA complex and the site and nature of interaction are studied. Drug interactions with quadruplex DNA were carried out in different potassium ionic strengths using fluorescence spectroscopy. It is found that fluorescence hypochromicity decreases with an increase in ionic strength in the case of TMPyP4, TMPyP3, and TMPyP2. Fluorescence titration studies and Job plots indicate that four molecules of TMPyP4, two molecules of TMPyP3 and TMPyP2 are interacting with one molecule of quadruplex DNA.

scholarly journals Interaction of TMPyP4, TMPyP3, and TMPyP2 with Intramolecular G-Quadruplex Formed by Promoter Region of Bcl2 and KRAS NHPPE

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Narayana Nagesh ◽  
Arumugam Ganesh Kumar
Keyword(s):  
Promoter Region ◽  
Dna Interaction ◽  
Predominant Role ◽  
Promoter Regions ◽  
Ligand Interaction ◽  
Quadruplex Dna ◽  
Molecular Binding ◽  
Quadruplex Structure ◽  
G Quadruplex ◽  
Structure Environment

Oncogenes are rich in guanine and capable of forming quadruplex structure. Promoter regions oncogenes such as Bcl2 and KRAS NHPPE are rich in guanine content and they can form quadruplex structures. Alterations in the mode and nature of molecular binding to DNA, certainly has effect on the posttranscriptional activities. Recent experiments indicate that structure of quadruplex complex and ligand has predominant role on ligand-quadruplex DNA interaction. In order to understand the nature of each ligand interaction with quadruplex DNA, Bcl2, KRAS NHPPE quadruplex DNA interaction with three porphyrin was studied using spectroscopy, microcalorimetry and mass spectrometry. Our studies, indicate that mode of ligand interaction varies with structure, environment and concentration of ligand. Fluorescence quenching experiments show that TMPyP4 interaction is ligand concentration dependent. Job plots and ITC experiments demonstrate that four molecules of TMPyP4 and two molecules of TMPyP3, TMPyP2 interact with each quadruplex complex. Through ITC titrations, ligand binding constant are higher for TMPyP4 (≈107 M−1) compared to TMPyP3, TMPyP2 (≈105 M−1). ESI-MS experiments confirm the stoichiometry of TMPyP4 : 39Bcl2 is 4 : 1 at saturation and it is 2 : 1 in case of KRAS NHPPE quadruplex.

scholarly journals A comparative study of the interactions of cationic hetarenes with quadruplex-DNA forming oligonucleotide sequences of the insulin-linked polymorphic region (ILPR)

2014 ◽  
Vol 10 ◽  
pp. 2963-2974 ◽  
Author(s):  
Darinka Dzubiel ◽  
Heiko Ihmels ◽  
Mohamed M A Mahmoud ◽  
Laura Thomas
Keyword(s):  
Comparative Study ◽  
Dna Sequences ◽  
Cd Spectroscopy ◽  
Thiazole Orange ◽  
Binding Parameters ◽  
Polymorphic Region ◽  
Quadruplex Dna ◽  
High Affinity

The interactions of the ILPR sequence (ILPR = "insulin-linked polymorphic region") a2 [d(ACAG4TGTG4ACAG4TGTG4)] with [2.2.2]heptamethinecyanine derivatives 1a–e and with the already established quadruplex ligands coralyne (2), 3,3′-[2,6-pyridinediylbis(carbonylimino)]bis[1-methylquinolinium] (3), 4,4′,4′′,4′′′-(21H,23H-porphine-5,10,15,20-tetrayl)tetrakis[1-methylpyridinium] (4), naphtho[2,1-b:3,4-b′:6,5-b′′:7,8-b′′′]tetraquinolizinium (5) and thiazole orange (6) were studied. It is demonstrated with absorption, fluorescence and CD spectroscopy that all investigated ligands bind with relatively high affinity to the ILPR-quadruplex DNA a2 (0.2–5.5 × 106 M−1) and that in most cases the binding parameters of ligand-ILPR complexes are different from the ones observed with other native quadruplex-forming DNA sequences.

PhenDV, a turn-off fluorescent quadruplex DNA probe for improving the sensitivity of drug screening assays

2017 ◽  
Vol 15 (34) ◽  
pp. 7117-7121 ◽  
Author(s):  
Claire Beauvineau ◽  
Corinne Guetta ◽  
Marie-Paule Teulade-Fichou ◽  
Florence Mahuteau-Betzer
Keyword(s):  
Drug Screening ◽  
Dna Probe ◽  
Quadruplex Dna ◽  
Affinity Ligands ◽  
High Affinity ◽  
G4 Dna ◽  
Screening Assays ◽  
Fluorescent Intercalator Displacement

PhenDV is a light-up probe for G4-fluorescent intercalator displacement. This potent G4-DNA binder discriminates between medium and high-affinity ligands.

scholarly journals Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

2021 ◽  
Vol 17 ◽  
pp. 991-1000
Author(s):  
Peter Jonas Wickhorst ◽  
Mathilda Blachnik ◽  
Denisa Lagumdzija ◽  
Heiko Ihmels
Keyword(s):  
Dna Binding ◽  
Coupling Reaction ◽  
Spectroscopic Studies ◽  
Binding Properties ◽  
Quadruplex Dna ◽  
G4 Dna ◽  
Fluorescence Light ◽  
Berberine Derivatives ◽  
Ct Dna ◽  
Dna Binding Properties

Eleven novel 10-O-aryl-substituted berberrubine and berberine derivatives were synthesized by the Cu2+-catalyzed Chan–Evans–Lam coupling of berberrubine with arylboronic acids and subsequent 9-O-methylation. The reaction is likely introduced by the Cu2+-induced demethylation of berberrubine and subsequent arylation of the resulting 10-oxyanion functionality. Thus, this synthetic route represents the first successful Cu-mediated coupling reaction of berberine substrates. The DNA-binding properties of the 10-O-arylberberine derivatives with duplex and quadruplex DNA were studied by thermal DNA denaturation experiments, spectrometric titrations as well as CD and LD spectroscopy. Fluorimetric DNA melting analysis with different types of quadruplex DNA revealed a moderate stabilization of the telomeric quadruplex-forming oligonucleotide sequence G3(TTAG3)3. The derivatives showed a moderate affinity towards quadruplex DNA (K b = 5–9 × 105 M−1) and ct DNA (K b = 3–5 × 104 M−1) and exhibited a fluorescence light-up effect upon complexation to both DNA forms, with slightly higher intensity in the presence of the quadruplex DNA. Furthermore, the CD- and LD-spectroscopic studies revealed that the title compounds intercalate into ct DNA and bind to G4-DNA by terminal stacking.

scholarly journals Human Rev1 relies on insert-2 to promote selective binding and accurate replication of stabilized G-quadruplex motifs

2021 ◽  
Author(s):  
Amit Ketkar ◽  
Lane Smith ◽  
Callie Johnson ◽  
Alyssa Richey ◽  
Makayla Berry ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mutation Frequency ◽  
Control Sequence ◽  
Wild Type ◽  
Binding Properties ◽  
High Affinity ◽  
G4 Dna ◽  
G Quadruplex ◽  
Forward Mutagenesis

Abstract We previously reported that human Rev1 (hRev1) bound to a parallel-stranded G-quadruplex (G4) from the c-MYC promoter with high affinity. We have extended those results to include other G4 motifs, finding that hRev1 exhibited stronger affinity for parallel-stranded G4 than either anti-parallel or hybrid folds. Amino acids in the αE helix of insert-2 were identified as being important for G4 binding. Mutating E466 and Y470 to alanine selectively perturbed G4 binding affinity. The E466K mutant restored wild-type G4 binding properties. Using a forward mutagenesis assay, we discovered that loss of hRev1 increased G4 mutation frequency >200-fold compared to the control sequence. Base substitutions and deletions occurred around and within the G4 motif. Pyridostatin (PDS) exacerbated this effect, as the mutation frequency increased >700-fold over control and deletions upstream of the G4 site more than doubled. Mutagenic replication of G4 DNA (±PDS) was partially rescued by wild-type and E466K hRev1. The E466A or Y470A mutants failed to suppress the PDS-induced increase in G4 mutation frequency. These findings have implications for the role of insert-2, a motif conserved in vertebrates but not yeast or plants, in Rev1-mediated suppression of mutagenesis during G4 replication.

scholarly journals ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Ching Teng ◽  
Aishwarya Sundaresan ◽  
Ryan O’Hara ◽  
Vincent U. Gant ◽  
Minhua Li ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Genome Stability ◽  
Helicase Domain ◽  
Quadruplex Dna ◽  
Heterochromatin Formation ◽  
Replicative Stress ◽  
G4 Dna ◽  
Mutation Burden ◽  
G Quadruplex ◽  
Dna Replication Stress

AbstractATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.

scholarly journals Control of bacterial nitrate assimilation by stabilization of G-quadruplex DNA

2016 ◽  
Vol 52 (92) ◽  
pp. 13511-13514 ◽  
Author(s):  
Zoë A. E. Waller ◽  
Benjamin J. Pinchbeck ◽  
Bhovina Seewoodharry Buguth ◽  
Timothy G. Meadows ◽  
David J. Richardson ◽  
...  
Keyword(s):  
Promoter Region ◽  
Paracoccus Denitrificans ◽  
Nitrate Assimilation ◽  
Quadruplex Dna ◽  
G Quadruplex ◽  
Specific Control

Ligand-specific control of nitrate assimilation inParacoccus denitrificansby stabilization of DNA G-quadruplex in the promoter region ofnas.

scholarly journals Subtle structural alterations in G-quadruplex DNA regulate site specificity of fluorescence light-up probes

2020 ◽  
Vol 48 (3) ◽  
pp. 1108-1119 ◽  
Author(s):  
Rajendra Kumar ◽  
Karam Chand ◽  
Sudipta Bhowmik ◽  
Rabindra Nath Das ◽  
Snehasish Bhattacharjee ◽  
...  
Keyword(s):  
Rational Design ◽  
Dna Structure ◽  
Biological Processes ◽  
Chemical Research ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Future Studies ◽  
G4 Dna ◽  
G Quadruplex ◽  
Fluorescence Light

Abstract G-quadruplex (G4) DNA structures are linked to key biological processes and human diseases. Small molecules that target specific G4 DNA structures and signal their presence would therefore be of great value as chemical research tools with potential to further advance towards diagnostic and therapeutic developments. However, the development of these types of specific compounds remain as a great challenge. In here, we have developed a compound with ability to specifically signal a certain c-MYC G4 DNA structure through a fluorescence light-up mechanism. Despite the compound's two binding sites on the G4 DNA structure, only one of them result in the fluorescence light-up effect. This G-tetrad selectivity proved to originate from a difference in flexibility that affected the binding affinity and tilt the compound out of the planar conformation required for the fluorescence light-up mechanism. The intertwined relation between the presented factors is likely the reason for the lack of examples using rational design to develop compounds with turn-on emission that specifically target certain G4 DNA structures. However, this study shows that it is indeed possible to develop such compounds and present insights into the molecular details of specific G4 DNA recognition and signaling to advance future studies of G4 biology.

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