CADD-27. G-QUADRUPLEX DNA DRIVES GENOMIC INSTABILITY AND REPRESENTS A TARGETABLE MOLECULAR ABNORMALITY IN ATRX-DEFICIENT MALIGNANT GLIOMA

AbstractMutational inactivation of ATRX (α-thalassemia mental retardation X-linked) represents a defining molecular alteration in large subsets of malignant glioma. Yet the pathogenic consequences of ATRX deficiency remain unclear, as do tractable mechanisms for its therapeutic targeting. Here we report that ATRX loss in isogenic glioma model systems induces replication stress and DNA damage by way of G-quadruplex (G4) DNA secondary structure. Moreover, these effects are associated with the acquisition of disease-relevant copy number alterations over time. We then demonstrate, both in vitro and in vivo, that ATRX deficiency selectively enhances DNA damage and cell death following chemical G4 stabilization. Finally, we show that G4 stabilization synergizes with other DNA-damaging therapies, including ionizing radiation, in the ATRX-deficient context. Our findings reveal novel pathogenic mechanisms driven by ATRX deficiency in glioma, while also pointing to tangible strategies for drug development.

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Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli

Microorganisms ◽

10.3390/microorganisms8010028 ◽

2019 ◽

Vol 8 (1) ◽

pp. 28 ◽

Cited By ~ 2

Author(s):

Virali J. Parekh ◽

Brittany A. Niccum ◽

Rachna Shah ◽

Marisa A. Rivera ◽

Mark J. Novak ◽

...

Keyword(s):

Genomic Instability ◽

Dna Repeats ◽

Loop Formation ◽

Bacterial Gene ◽

Quadruplex Dna ◽

E Coli ◽

Alternative Structures ◽

Bacterial Gene Expression ◽

G Quadruplex

Certain G-rich DNA repeats can form quadruplex in bacterial chromatin that can present blocks to DNA replication and, if not properly resolved, may lead to mutations. To understand the participation of quadruplex DNA in genomic instability in Escherichia coli (E. coli), mutation rates were measured for quadruplex-forming DNA repeats, including (G3T)4, (G3T)8, and a RET oncogene sequence, cloned as the template or nontemplate strand. We evidence that these alternative structures strongly influence mutagenesis rates. Precisely, our results suggest that G-quadruplexes form in E. coli cells, especially during transcription when the G-rich strand can be displaced by R-loop formation. Structure formation may then facilitate replication misalignment, presumably associated with replication fork blockage, promoting genomic instability. Furthermore, our results also evidence that the nucleoid-associated protein Hfq is involved in the genetic instability associated with these sequences. Hfq binds and stabilizes G-quadruplex structure in vitro and likely in cells. Collectively, our results thus implicate quadruplexes structures and Hfq nucleoid protein in the potential for genetic change that may drive evolution or alterations of bacterial gene expression.

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Hybrid Imidazole-Pyridine Derivatives: An Approach to Novel Anticancer DNA Intercalators

Current Medicinal Chemistry ◽

10.2174/0929867326666181220094229 ◽

2020 ◽

Vol 27 (1) ◽

pp. 154-169 ◽

Cited By ~ 7

Author(s):

Claudiu N. Lungu ◽

Bogdan Ionel Bratanovici ◽

Maria Mirabela Grigore ◽

Vasilichia Antoci ◽

Ionel I. Mangalagiu

Keyword(s):

Experimental Data ◽

Antimicrobial Properties ◽

Qsar Model ◽

Therapeutic Effectiveness ◽

Computational Results ◽

Pyridine Derivatives ◽

Quadruplex Dna ◽

Dna Intercalators ◽

Structure Activity ◽

G Quadruplex

Lack of specificity and subsequent therapeutic effectiveness of antimicrobial and antitumoral drugs is a common difficulty in therapy. The aim of this study is to investigate, both by experimental and computational methods, the antitumoral and antimicrobial properties of a series of synthesized imidazole-pyridine derivatives. Interaction with three targets was discussed: Dickerson-Drew dodecamer (PDB id 2ADU), G-quadruplex DNA string (PDB id 2F8U) and DNA strain in complex with dioxygenase (PDB id 3S5A). Docking energies were computed and represented graphically. On them, a QSAR model was developed in order to further investigate the structure-activity relationship. Results showed that synthesized compounds have antitumoral and antimicrobial properties. Computational results agreed with the experimental data.

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Emerging Role of G-quadruplex DNA as Target in Anticancer Therapy

Current Pharmaceutical Design ◽

10.2174/1381612822666160831101031 ◽

2017 ◽

Vol 22 (44) ◽

pp. 6612-6624 ◽

Cited By ~ 35

Author(s):

Graziella Cimino-Reale ◽

Nadia Zaffaroni ◽

Marco Folini

Keyword(s):

Anticancer Therapy ◽

Quadruplex Dna ◽

G Quadruplex

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The Functional Role of Loops and Flanking Sequences of G-Quadruplex Aptamer to the Hemagglutinin of Influenza a Virus

International Journal of Molecular Sciences ◽

10.3390/ijms22052409 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2409

Author(s):

Anastasia A. Bizyaeva ◽

Dmitry A. Bunin ◽

Valeria L. Moiseenko ◽

Alexandra S. Gambaryan ◽

Sonja Balk ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Core Structure ◽

Dna Aptamer ◽

Tertiary Structures ◽

Quadruplex Dna ◽

G Quadruplex ◽

Flanking Sequences ◽

Related Proteins

Nucleic acid aptamers are generally accepted as promising elements for the specific and high-affinity binding of various biomolecules. It has been shown for a number of aptamers that the complexes with several related proteins may possess a similar affinity. An outstanding example is the G-quadruplex DNA aptamer RHA0385, which binds to the hemagglutinins of various influenza A virus strains. These hemagglutinins have homologous tertiary structures but moderate-to-low amino acid sequence identities. Here, the experiment was inverted, targeting the same protein using a set of related, parallel G-quadruplexes. The 5′- and 3′-flanking sequences of RHA0385 were truncated to yield parallel G-quadruplex with three propeller loops that were 7, 1, and 1 nucleotides in length. Next, a set of minimal, parallel G-quadruplexes with three single-nucleotide loops was tested. These G-quadruplexes were characterized both structurally and functionally. All parallel G-quadruplexes had affinities for both recombinant hemagglutinin and influenza virions. In summary, the parallel G-quadruplex represents a minimal core structure with functional activity that binds influenza A hemagglutinin. The flanking sequences and loops represent additional features that can be used to modulate the affinity. Thus, the RHA0385–hemagglutinin complex serves as an excellent example of the hypothesis of a core structure that is decorated with additional recognizing elements capable of improving the binding properties of the aptamer.

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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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