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International Journal of Molecular... Sep 2021G-quadruplexes constitute an important type of nucleic acid structure, which can be found in living cells and applied by cell machinery as pivotal regulatory elements.... (Review)
Review
G-quadruplexes constitute an important type of nucleic acid structure, which can be found in living cells and applied by cell machinery as pivotal regulatory elements. Importantly, robust development of SELEX technology and modern, nucleic acid-based therapeutic strategies targeted towards various molecules have also revealed a large group of potent aptamers whose structures are grounded in G-quadruplexes. In this review, we analyze further extension of tetraplexes by additional structural elements and investigate whether G-quadruplex junctions with duplex, hairpin, triplex, or second G-quadruplex motifs are favorable for aptamers stability and biological activity. Furthermore, we indicate the specific and pivotal role of the G-quadruplex domain and the additional structural elements in interactions with target molecules. Finally, we consider the potency of G-quadruplex junctions in future applications and indicate the emerging research area that is still waiting for development to obtain highly specific and effective nucleic acid-based molecular tools.
Topics: Aptamers, Nucleotide; Base Sequence; G-Quadruplexes; Humans; Nucleotide Motifs
PubMed: 34576112
DOI: 10.3390/ijms22189948 -
Biomolecules Oct 2021G-quadruplexes (G4s) are stable secondary nucleic acid structures that play crucial roles in many fundamental biological processes. The folding/unfolding dynamics of G4... (Review)
Review
G-quadruplexes (G4s) are stable secondary nucleic acid structures that play crucial roles in many fundamental biological processes. The folding/unfolding dynamics of G4 structures are associated with the replication and transcription regulation functions of G4s. However, many DNA G4 sequences can adopt a variety of topologies and have complex folding/unfolding dynamics. Determining the dynamics of G4s and their regulation by proteins remains challenging due to the coexistence of multiple structures in a heterogeneous sample. Here, in this mini-review, we introduce the application of single-molecule force-spectroscopy methods, such as magnetic tweezers, optical tweezers, and atomic force microscopy, to characterize the polymorphism and folding/unfolding dynamics of G4s. We also briefly introduce recent studies using single-molecule force spectroscopy to study the molecular mechanisms of G4-interacting proteins.
Topics: DNA; G-Quadruplexes; Optical Tweezers; Promoter Regions, Genetic
PubMed: 34827577
DOI: 10.3390/biom11111579 -
The Journal of Physical Chemistry... Mar 2024G-quadruplexes (G4s) are nucleic acid structures crucial for the regulation of gene expression and genome maintenance. While they hold promise as nanodevice components,...
G-quadruplexes (G4s) are nucleic acid structures crucial for the regulation of gene expression and genome maintenance. While they hold promise as nanodevice components, achieving desired G4 folds requires understanding the interplay between stability and structural properties, like helicity. Although right-handed G4 structures dominate the experimental data, the molecular basis for this preference over left-handed helicity is unclear. To address this, we employ all-atom molecular dynamics simulations and quantum chemical methods. Our results reveal that right-handed G4s exhibit greater thermodynamic and kinetic stability as a result of favorable sugar-phosphate backbone conformations in guanine tracts. Moreover, while hydrogen-bonding patterns influence helicity-specific G4 loop conformations, they minimally affect stability differences. We also elucidate the strong correlation between helicity and the strand progression direction, essential for G4 structures. These findings deepen our understanding of G4s, providing molecular-level insights into their structural and energetic preferences, which could inform the design of novel nanodevices.
Topics: G-Quadruplexes; Nucleic Acids; Molecular Dynamics Simulation; Thermodynamics
PubMed: 38477716
DOI: 10.1021/acs.jpclett.3c03589 -
Molecules (Basel, Switzerland) Oct 2021The non-coding RNAs (ncRNA) are RNA transcripts with different sizes, structures and biological functions that do not encode functional proteins. RNA G-quadruplexes... (Review)
Review
The non-coding RNAs (ncRNA) are RNA transcripts with different sizes, structures and biological functions that do not encode functional proteins. RNA G-quadruplexes (rG4s) have been found in small and long ncRNAs. The existence of an equilibrium between rG4 and stem-loop structures in ncRNAs and its effect on biological processes remains unexplored. For example, deviation from the stem-loop leads to deregulated mature miRNA levels, demonstrating that miRNA biogenesis can be modulated by ions or small molecules. In light of this, we report several examples of rG4s in certain types of ncRNAs, and the implications of G4 stabilization using small molecules, also known as G4 ligands, in the regulation of gene expression, miRNA biogenesis, and miRNA-mRNA interactions. Until now, different G4 ligands scaffolds were synthesized for these targets. The regulatory role of the above-mentioned rG4s in ncRNAs can be used as novel therapeutic approaches for adjusting miRNA levels.
Topics: G-Quadruplexes; Humans; Inverted Repeat Sequences; Ligands; MicroRNAs; RNA, Messenger; RNA, Untranslated
PubMed: 34684745
DOI: 10.3390/molecules26206164 -
Frontiers in Immunology 2022The chronic infection with hepatitis B virus (HBV) is an important health problem that affects millions of people worldwide. Current therapies for HBV always suffer from... (Review)
Review
The chronic infection with hepatitis B virus (HBV) is an important health problem that affects millions of people worldwide. Current therapies for HBV always suffer from a poor response rate, common side effects, and the need for lifelong treatment. Novel therapeutic targets are expected. Interestingly, non-canonical structures of nucleic acids play crucial roles in the regulation of gene expression. Especially the formation of G-quadruplexes (G4s) in G-rich strands has been demonstrated to affect many bioprocesses including replication, transcription, and translation, showing great potential as targets in anticancer and antiviral therapies. In this review, we summarize recent antiviral studies about G4s and discuss the potential roles of G4 structures in antiviral therapy for HBV.
Topics: Humans; G-Quadruplexes; Hepatitis B virus; Antiviral Agents
PubMed: 36591216
DOI: 10.3389/fimmu.2022.1091873 -
Chemical Communications (Cambridge,... Nov 2022Guanine-rich DNA sequences are known to fold into secondary structures called G-quadruplexes (G4s), which can form from either individual DNA strands (intra-molecular)... (Review)
Review
Guanine-rich DNA sequences are known to fold into secondary structures called G-quadruplexes (G4s), which can form from either individual DNA strands (intra-molecular) or multiple DNA strands (inter-molecular, iG4s). Intra-molecular G4s have been the object of extensive biological investigation due to their enrichment in gene-promoters and telomers. On the other hand, iG4s have never been considered in biological contexts, as the interaction between distal sequences of DNA to form an iG4 in cells was always deemed as highly unlikely. In this feature article, we challenge this dogma by presenting our recent discovery of the first human protein (CSB) displaying astonishing picomolar affinity and binding selectivity for iG4s. These findings suggest potential for iG4 structures to form in cells and highlight the need of further studies to unravel the fundamental biological roles of these inter-molecular DNA structures. Furthermore, we discuss how the potential for formation of iG4s in neuronal cells, triggered by repeat expansions in the gene, can lead to the formation of nucleic-acids based pathological aggregates in neurodegenerative diseases like ALS and FTD. Finally, based on our recent work on short LNA-modified probes, we provide a prespective on how the rational design of G4-selective chemical tools can be leveraged to further elucidate the biological relevance of iG4 structures in the context of ageing-related diseases.
Topics: Humans; G-Quadruplexes; DNA; Telomere; Guanine; Molecular Structure
PubMed: 36281554
DOI: 10.1039/d2cc04872h -
Nucleic Acids Research Apr 2021Noncoding RNAs are functional transcripts that are not translated into proteins. They represent the largest portion of the human transcriptome and have been shown to... (Review)
Review
Noncoding RNAs are functional transcripts that are not translated into proteins. They represent the largest portion of the human transcriptome and have been shown to regulate gene expression networks in both physiological and pathological cell conditions. Research in this field has made remarkable progress in the comprehension of how aberrations in noncoding RNA drive relevant disease-associated phenotypes; however, the biological role and mechanism of action of several noncoding RNAs still need full understanding. Besides fulfilling its function through sequence-based mechanisms, RNA can form complex secondary and tertiary structures which allow non-canonical interactions with proteins and/or other nucleic acids. In this context, the presence of G-quadruplexes in microRNAs and long noncoding RNAs is increasingly being reported. This evidence suggests a role for RNA G-quadruplexes in controlling microRNA biogenesis and mediating noncoding RNA interaction with biological partners, thus ultimately regulating gene expression. Here, we review the state of the art of G-quadruplexes in the noncoding transcriptome, with their structural and functional characterization. In light of the existence and further possible development of G-quadruplex binders that modulate G-quadruplex conformation and protein interactions, we also discuss the therapeutic potential of G-quadruplexes as targets to interfere with disease-associated noncoding RNAs.
Topics: G-Quadruplexes; Gene Expression Regulation; Humans; RNA, Untranslated; Transcriptome
PubMed: 33721024
DOI: 10.1093/nar/gkab127 -
Current Protocols in Nucleic Acid... Sep 2012Although DNA is most widely known for its ability to store and pass along genetic information, the discovery of G-quadruplex structures has illuminated a new role for... (Review)
Review
Although DNA is most widely known for its ability to store and pass along genetic information, the discovery of G-quadruplex structures has illuminated a new role for DNA in biology. DNA G-quadruplexes are four-stranded globular nucleic acid secondary structures formed in specific G-rich sequences with biological significance, such as human telomeres and oncogene promoters. This review focuses on the unimolecular DNA G-quadruplexes, which can readily form in solution under physiological conditions and are considered to be the most biologically relevant. Available structural data show a great conformational diversity of unimolecular G-quadruplexes, which are amenable to small-molecule drug targeting. The relationships between sequence, structure, and stability of unimolecular DNA G-quadruplexes, as well as the recent progress on interactions with small-molecule compounds and insights into rational design of G-quadruplex-interactive molecules, will be discussed.
Topics: Alkaloids; Base Pairing; Base Sequence; DNA; G-Quadruplexes; Humans; Hydrogen Bonding; Indoles; Models, Molecular; Promoter Regions, Genetic; Quinolines; Telomere
PubMed: 22956454
DOI: 10.1002/0471142700.nc1705s50 -
Scientific Reports Jan 2024G-quadruplex (G4) structures have emerged as singular therapeutic targets for cancer and neurodegeneration. Autophagy, a crucial homeostatic mechanism of the cell, is...
G-quadruplex (G4) structures have emerged as singular therapeutic targets for cancer and neurodegeneration. Autophagy, a crucial homeostatic mechanism of the cell, is often dysregulated in neurodegenerative diseases and cancers. We used QGRS mapper to identify 470 G4 sequences in MTOR, a key negative regulator of autophagy. We sought to identify a functional context by leveraging the effect of G4-targeting ligands on MTOR G4 sequences. The effect of Bis-4,3, a G4 selective dimeric carbocyanine dye, was compared with the known G4-stabilizing activity of the porphyrin, TMPyP4 in HeLa and SHSY-5Y cells. Our results show that treatment with G4-selective ligands downregulates MTOR RNA and mTOR protein expression levels. This is the first report describing G4 motifs in MTOR. This study indicates a possible role of G4 stabilizing ligands in induction of autophagy by downregulation of mTOR levels, albeit not precluding MTOR independent pathways.
Topics: Humans; G-Quadruplexes; RNA; TOR Serine-Threonine Kinases; HeLa Cells; Autophagy; Ligands
PubMed: 38291093
DOI: 10.1038/s41598-024-52561-y -
Molecules (Basel, Switzerland) Mar 2019G-quadruplexes are made up of guanine-rich RNA and DNA sequences capable of forming noncanonical nucleic acid secondary structures. The base-specific sterical... (Review)
Review
G-quadruplexes are made up of guanine-rich RNA and DNA sequences capable of forming noncanonical nucleic acid secondary structures. The base-specific sterical configuration of G-quadruplexes allows the stacked G-tetrads to bind certain planar molecules like hemin (iron (III)-protoporphyrin IX) to regulate enzymatic-like functions such as peroxidase-mimicking activity, hence the use of the term DNAzyme/RNAzyme. This ability has been widely touted as a suitable substitute to conventional enzymatic reporter systems in diagnostics. This review will provide a brief overview of the G-quadruplex architecture as well as the many forms of reporter systems ranging from absorbance to luminescence readouts in various platforms. Furthermore, some challenges and improvements that have been introduced to improve the application of G-quadruplex in diagnostics will be highlighted. As the field of diagnostics has evolved to apply different detection systems, the need for alternative reporter systems such as G-quadruplexes is also paramount.
Topics: Colorimetry; DNA, Catalytic; G-Quadruplexes; Humans; Luminescence; Nucleic Acid Conformation
PubMed: 30893817
DOI: 10.3390/molecules24061079