Antitumor substitution-inert polynuclear platinum complexes stabilize G-quadruplex DNA and suppress G-quadruplex-mediated gene expression

2021 ◽  
Author(s):  
Jaroslav Malina ◽  
Hana Kostrhunova ◽  
Nicholas Patrick Farrell ◽  
Viktor Brabec
Keyword(s):  
Gene Expression ◽  
Drug Targets ◽  
Platinum Complexes ◽  
Anticancer Therapy ◽  
Promoter Regions ◽  
Quadruplex Dna ◽  
G Quadruplex

DNA G-quadruplex (G4) structures formed in the telomeric and promoter regions represent attractive drug targets for anticancer therapy. Thus, much effort has been devoted to the development of a variety...

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

2017 ◽  
Vol 22 (44) ◽  
pp. 6612-6624 ◽  
Author(s):  
Graziella Cimino-Reale ◽  
Nadia Zaffaroni ◽  
Marco Folini
Keyword(s):  
Anticancer Therapy ◽  
Quadruplex Dna ◽  
G Quadruplex

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 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.

Insights of potential G-quadruplex sequences in telomeres and proto-oncogenes

2013 ◽  
Vol 21 (3-4) ◽  
pp. 118-124 ◽  
Author(s):  
Rajendra Bhadane ◽  
Rupali Bhadane ◽  
Dhananjay Meshram
Keyword(s):  
Gene Expression ◽  
Transcription Initiation ◽  
Binding Proteins ◽  
Promoter Regions ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
G Quadruplex ◽  
Anticancer Target ◽  
Stable Structures

Guanine rich sequences have the ability to fold into stable 4 stranded structures called G-quadruplex under physiological concentrations of Na+ or K+. G-quadruplexes are found in telomeres, being stable structures under the control of telomerase binding proteins. They are also identified throughout the genome and are enriched in promoter regions of protein coding genes, upstream and downstream of the transcription initiation sites. A number of these promoter quadruplexes have been investigated for several proto-oncogenes. The formation of these quadruplexes can lead to chemical intervention of gene expression using a G-quadruplex binding ligand. We review location, configuration, and stabilization of these quadruplexes in some of the important promoters with regards to their potential as anticancer target.

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 Self-assembled Pt2L2 boxes strongly bind G-quadruplex DNA and influence gene expression in cancer cells

2017 ◽  
Vol 46 (2) ◽  
pp. 329-332 ◽  
Author(s):  
O. Domarco ◽  
D. Lötsch ◽  
J. Schreiber ◽  
C. Dinhof ◽  
S. Van Schoonhoven ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Quadruplex Dna ◽  
Dna Motifs ◽  
Size Dependent ◽  
G Quadruplex ◽  
Self Assembled ◽  
Influence Gene Expression

Pt(ii) boxes bind native and G-quadruplex DNA motifs in a size-dependent fashion and influence the expression of G-quadruplex forming genes.

scholarly journals The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

2021 ◽  
Vol 14 (2) ◽  
pp. 96
Author(s):  
Susie L. Brown ◽  
Samantha Kendrick
Keyword(s):  
Gene Expression ◽  
Secondary Structure ◽  
Biological Function ◽  
Molecular Target ◽  
Therapeutic Approaches ◽  
Promoter Regions ◽  
New Therapeutic Approaches ◽  
G Quadruplex ◽  
Dna Elements ◽  
Insight Into

Stretches of cytosine-rich DNA are capable of adopting a dynamic secondary structure, the i-motif. When within promoter regions, the i-motif has the potential to act as a molecular switch for controlling gene expression. However, i-motif structures in genomic areas of repetitive nucleotide sequences may play a role in facilitating or hindering expansion of these DNA elements. Despite research on the i-motif trailing behind the complementary G-quadruplex structure, recent discoveries including the identification of a specific i-motif antibody are pushing this field forward. This perspective reviews initial and current work characterizing the i-motif and providing insight into the biological function of this DNA structure, with a focus on how the i-motif can serve as a molecular target for developing new therapeutic approaches to modulate gene expression and extension of repetitive DNA.

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

2020 ◽  
Author(s):  
Anirban Ghosh ◽  
Eric Largy ◽  
Valérie Gabelica
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Drug Binding ◽  
Quadruplex Dna ◽  
Link Type ◽  
Nmr Structures ◽  
G Quadruplex ◽  
Screening Assays

ABSTRACTG-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) K+, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM TMAA. 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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