scholarly journals NMR solution and X-ray crystal structures of a DNA molecule containing both right- and left-handed parallel-stranded G-quadruplexes

2019 ◽  
Vol 47 (15) ◽  
pp. 8272-8281 ◽  
Author(s):  
Fernaldo Richtia Winnerdy ◽  
Blaž Bakalar ◽  
Arijit Maity ◽  
J Jeya Vandana ◽  
Yves Mechulam ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Double Helix ◽  
Quadruple Helix ◽  
Single Nucleotide ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
X Ray ◽  
Left Handed ◽  
G Quadruplex ◽  
Quadruplex Formation

AbstractAnalogous to the B- and Z-DNA structures in double-helix DNA, there exist both right- and left-handed quadruple-helix (G-quadruplex) DNA. Numerous conformations of right-handed and a few left-handed G-quadruplexes were previously observed, yet they were always identified separately. Here, we present the NMR solution and X-ray crystal structures of a right- and left-handed hybrid G-quadruplex. The structure reveals a stacking interaction between two G-quadruplex blocks with different helical orientations and displays features of both right- and left-handed G-quadruplexes. An analysis of loop mutations suggests that single-nucleotide loops are preferred or even required for the left-handed G-quadruplex formation. The discovery of a right- and left-handed hybrid G-quadruplex further expands the polymorphism of G-quadruplexes and is potentially useful in designing a left-to-right junction in G-quadruplex engineering.

scholarly journals Structure of a left-handed DNA G-quadruplex

2015 ◽  
Vol 112 (9) ◽  
pp. 2729-2733 ◽  
Author(s):  
Wan Jun Chung ◽  
Brahim Heddi ◽  
Emmanuelle Schmitt ◽  
Kah Wai Lim ◽  
Yves Mechulam ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Double Helix ◽  
X Ray ◽  
Cellular Processes ◽  
Quadruplex Structure ◽  
Left Handed ◽  
G Quadruplex ◽  
Recognition Elements ◽  
Diagnostic Applications

Aside from the well-known double helix, DNA can also adopt an alternative four-stranded structure known as G-quadruplex. Implications of such a structure in cellular processes, as well as its therapeutic and diagnostic applications, have been reported. The G-quadruplex structure is highly polymorphic, but so far, only right-handed helical forms have been observed. Here we present the NMR solution and X-ray crystal structures of a left-handed DNA G-quadruplex. The structure displays unprecedented features that can be exploited as unique recognition elements.

scholarly journals Repair of O6-methylguanine adducts in human telomeric G-quadruplex DNA by O6-alkylguanine-DNA alkyltransferase

2014 ◽  
Vol 42 (15) ◽  
pp. 9781-9791 ◽  
Author(s):  
Lance M. Hellman ◽  
Tyler J. Spear ◽  
Colton J. Koontz ◽  
Manana Melikishvili ◽  
Michael G. Fried
Keyword(s):  
Conformational Dynamics ◽  
Rapid Phase ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Ability To Act ◽  
Telomere Sequence ◽  
G Quadruplex ◽  
Dna Alkyltransferase ◽  
Quadruplex Formation ◽  
Dna Substrate

Abstract O 6-alkylguanine-DNA alkyltransferase (AGT) is a single-cycle DNA repair enzyme that removes pro-mutagenic O6-alkylguanine adducts from DNA. Its functions with short single-stranded and duplex substrates have been characterized, but its ability to act on other DNA structures remains poorly understood. Here, we examine the functions of this enzyme on O6-methylguanine (6mG) adducts in the four-stranded structure of the human telomeric G-quadruplex. On a folded 22-nt G-quadruplex substrate, binding saturated at 2 AGT:DNA, significantly less than the ∼5 AGT:DNA found with linear single-stranded DNAs of similar length, and less than the value found with the telomere sequence under conditions that inhibit quadruplex formation (4 AGT:DNA). Despite these differences, AGT repaired 6mG adducts located within folded G-quadruplexes, at rates that were comparable to those found for a duplex DNA substrate under analogous conditions. Repair was kinetically biphasic with the amplitudes of rapid and slow phases dependent on the position of the adduct within the G-quadruplex: in general, adducts located in the top or bottom tetrads of a quadruplex stack exhibited more rapid-phase repair than did adducts located in the inner tetrad. This distinction may reflect differences in the conformational dynamics of 6mG residues in G-quadruplex DNAs.

scholarly journals DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions

2021 ◽  
Author(s):  
Anirban Ghosh ◽  
Eric Largy ◽  
Valérie Gabelica
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Drug Binding ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Nmr Structures ◽  
G Quadruplex ◽  
Screening Assays

Abstract G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually ∼100 mM) potassium, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM trimethylammonium acetate. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in the g4dbr package (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).

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.

scholarly journals A Minimal Sequence for Left‐Handed G‐Quadruplex Formation

2019 ◽  
Vol 58 (8) ◽  
pp. 2331-2335 ◽  
Author(s):  
Blaž Bakalar ◽  
Brahim Heddi ◽  
Emmanuelle Schmitt ◽  
Yves Mechulam ◽  
Anh Tuân Phan
Keyword(s):  
Left Handed ◽  
G Quadruplex ◽  
Quadruplex Formation ◽  
Minimal Sequence

scholarly journals A Minimal Sequence for Left-Handed G-Quadruplex Formation

2019 ◽  
Vol 131 (8) ◽  
pp. 2353-2357 ◽  
Author(s):  
Blaž Bakalar ◽  
Brahim Heddi ◽  
Emmanuelle Schmitt ◽  
Yves Mechulam ◽  
Anh Tuân Phan
Keyword(s):  
Left Handed ◽  
G Quadruplex ◽  
Quadruplex Formation ◽  
Minimal Sequence

scholarly journals Impact of a Single Nucleotide Change or Non-Nucleoside Modifications in G-Rich Region on the Quadruplex–Duplex Hybrid Formation

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1236
Author(s):  
Dorota Gudanis ◽  
Karolina Zielińska ◽  
Daniel Baranowski ◽  
Ryszard Kierzek ◽  
Piotr Kozłowski ◽  
...  
Keyword(s):  
Target Sequence ◽  
Rich Region ◽  
Rna Sequences ◽  
Single Nucleotide ◽  
Alternative Structures ◽  
Single Nucleotide Change ◽  
G Quadruplex ◽  
Quadruplex Formation ◽  
Target Rna ◽  
Insight Into

In this paper, a method to discriminate between two target RNA sequences that differ by one nucleotide only is presented. The method relies on the formation of alternative structures, i.e., quadruplex–duplex hybrid (QDH) and duplex with dangling ends (Dss), after hybridization of DNA or RNA G-rich oligonucleotides with target sequences containing 5′–GGGCUGG–3′ or 5′–GGGCGGG–3′ fragments. Using biophysical methods, we studied the effect of oligonucleotide types (DNA, RNA), non-nucleotide modifications (aliphatic linkers or abasic), and covalently attached G4 ligand on the ability of G-rich oligonucleotides to assemble a G-quadruplex motif. We demonstrated that all examined non-nucleotide modifications could mimic the external loops in the G-quadruplex domain of QDH structures without affecting their stability. Additionally, some modifications, in particular the presence of two abasic residues in the G-rich oligonucleotide, can induce the formation of non-canonical QDH instead of the Dss structure upon hybridization to a target sequence containing the GGGCUGG motif. Our results offer new insight into the sequential requirements for the formation of G-quadruplexes and provide important data on the effects of non-nucleotide modifications on G-quadruplex formation.

scholarly journals Specific Photocleavage Activity of N ‐Methylmesoporphyrin IX on G‐Quadruplex DNA Structures

2019 ◽  
Vol 33 (S1) ◽  
Author(s):  
Ruby A Escobedo ◽  
Kimberly J Long ◽  
Dominic N McBrayer ◽  
Michelle Schoonover ◽  
Sean M Kerwin
Keyword(s):  
Quadruplex Dna ◽  
Dna Structures ◽  
G Quadruplex
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