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

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.

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

Nucleic Acids Research ◽

10.1093/nar/gkz349 ◽

2019 ◽

Vol 47 (15) ◽

pp. 8272-8281 ◽

Cited By ~ 5

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.

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

Nucleic Acids Research ◽

10.1093/nar/gkab039 ◽

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).

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G-quadruplex DNA structures and their relevance in radioprotection

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/j.bbagen.2021.129857 ◽

2021 ◽

Vol 1865 (5) ◽

pp. 129857

Author(s):

Nitu Kumari ◽

Sathees C. Raghavan

Keyword(s):

Quadruplex Dna ◽

Dna Structures ◽

G Quadruplex

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

Nucleic Acids Research ◽

10.1093/nar/gkz1205 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1108-1119 ◽

Cited By ~ 5

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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G-Quadruplex Dna Structures And Site Specific Genetic Instability

10.30707/etd2015.williams.j ◽

2015 ◽

Author(s):

Jonathan David Williams

Keyword(s):

Genetic Instability ◽

Site Specific ◽

Quadruplex Dna ◽

Dna Structures ◽

G Quadruplex

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

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.471.5 ◽

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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Selective Interactions with Various G-Quadruplex DNA Forming Sequences by Berberine and Palmatine Analogues

10.20944/preprints201805.0189.v1 ◽

2018 ◽

Author(s):

Marco Franceschin ◽

Lorenzo Cianni ◽

Massimo Pitorri ◽

Emanuela Micheli ◽

Stefano Cacchione ◽

...

Keyword(s):

Anticancer Drugs ◽

Natural Compounds ◽

Side Chains ◽

Quadruplex Dna ◽

G Quadruplex ◽

Quadruplex Formation ◽

Selective Interactions

In this article/review, the selective interactions of several berberine and palmatine derivatives with various DNA G-quadruplex structures are reported. These derivatives were constructed starting from two natural compounds, berberine and palamatine, through specific synthetic passages following two different schemes for each of them and using several substituents. The details of these synthesis are also described. Indeed, the study of the interactions of these derivative compounds with various G-quadruplex forming sequences was carried out by means of various structural and biochemical techniques. The results show that the presence of suitable side chains are very useful to improve the interaction of the ligands with G-quadruplex structures. Thus, since G-quadruplex formation is promoted by these compounds, which have never been reported before, these may be tested as potential anticancer drugs.

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Controlling anticancer drug mediated G-quadruplex formation and stabilization by a molecular container

Physical Chemistry Chemical Physics ◽

10.1039/c8cp00325d ◽

2018 ◽

Vol 20 (11) ◽

pp. 7808-7818 ◽

Cited By ~ 4

Author(s):

Sagar Satpathi ◽

Reman K. Singh ◽

Arnab Mukherjee ◽

Partha Hazra

Keyword(s):

Anticancer Drug ◽

Quadruplex Dna ◽

Emission Color ◽

Molecular Container ◽

G Quadruplex ◽

Quadruplex Formation

G-quadruplex DNA (GQ-DNA) formation has been controlled using a molecular container, cucurbit[7]uril (CB7), by means of translocating a potential anticancer drug, topotecan, from GQ-DNA to the CB7 nanocavity. Interestingly, this whole cycle can be easily monitored through the change in the emission color of the stabilizing ligand, i.e., topotecan.

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N-methyl mesoporphyrin IX as a highly selective light-up probe for G-quadruplex DNA

Journal of Porphyrins and Phthalocyanines ◽

10.1142/s1088424619300179 ◽

2019 ◽

Vol 23 (11n12) ◽

pp. 1195-1215 ◽

Cited By ~ 5

Author(s):

Ariana Yett ◽

Linda Yingqi Lin ◽

Dana Beseiso ◽

Joanne Miao ◽

Liliya A. Yatsunyk

Keyword(s):

Optical Properties ◽

Small Molecules ◽

Genomic Stability ◽

Water Soluble ◽

Biological Processes ◽

Binding Properties ◽

Quadruplex Dna ◽

Dna Structures ◽

G Quadruplex ◽

High Fluorescence

[Formula: see text]-methyl mesoporphyrin IX (NMM) is a water-soluble, non-symmetric porphyrin with excellent optical properties and unparalleled selectivity for G-quadruplex (GQ) DNA. G-quadruplexes are non-canonical DNA structures formed by guanine-rich sequences. They are implicated in genomic stability, longevity, and cancer. The ability of NMM to selectively recognize GQ structures makes it a valuable scaffold for designing novel GQ binders. In this review, we survey the literature describing the GQ-binding properties of NMM as well as its wide utility in chemistry and biology. We start with the discovery of the GQ-binding properties of NMM and the development of NMM-binding aptamers. We then discuss the optical properties of NMM, focusing on the light-switch effect — high fluorescence of NMM induced upon its binding to GQ DNA. Additionally, we examine the affinity and selectivity of NMM for GQs, as well as its ability to stabilize GQ structures and favor parallel GQ conformations. Furthermore, a portion of the review is dedicated to the applications of NMM-GQ complexes as biosensors for heavy metals, small molecules ([Formula: see text] ATP and pesticides), DNA, and proteins. Finally and importantly, we discuss the utility of NMM as a probe to investigate the roles of GQs in biological processes.

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