Special Issue "Principles and Molecular Mechanisms of DNA and RNA G-Quadruplexes in Gene Regulation"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Nucleic Acids".

Deadline for manuscript submissions: closed (30 March 2022) | Viewed by 6627

Special Issue Editors

Assist. Prof. Pavel Ivanov
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Guest Editor
Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
Interests: posttranscriptional gene regulation; mRNA translation; tRNA; RNA granules; non-canonical nucleic acid structures
Special Issues, Collections and Topics in MDPI journals
Dr. Prakash Kharel
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Guest Editor
Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
Interests: RNA G-Quadruplexes (G4s) in Gene Regulation and Pathogenesis; G4s in Diagnostics and Therapeutics; Regulation of Repeat-Associated non-AUG Translation in Neurological Disorders
Dr. Anna Varizhuk
E-Mail Website
Guest Editor
Department of Biophysics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical-Biological Agency, and Moscow Institute of Physics and Technology, Moscow, Russia
Interests: G-Quadruplexe (G4) and i-Motif (iM) DNA structures; G4/iM-interacting proteins; gene expression regulation; development of im-based biosensors; G4 contributions to Chromatin Looping
Dr. Valentina Pirota
E-Mail Website
Guest Editor
Department of Chemistry, University of Pavia, Pavia, Italy
Interests: development of novel gene strategies based on selective recognition and stabilization of DNA and RNA G4s for cancer, HIV-1, and neurodegenerative diseases; peptide nucleic acids; characterization of G4’s irreversible modifications; catalytic metallodrugs

Special Issue Information

Dear Colleagues,

Guanine quadruplexes (G4s) are non-canonical four-stranded structures that can be formed in guanine (G)-rich nucleic acid sequences. Numerous G-rich sequences capable of forming G4 structures have been described, mostly based on in vitro studies, and evidence supporting their existence in vivo continues to grow. The distribution of putative G4s across the various regulatory regions of the genome and transcriptome immediately hints at the potential impact of G4s on cellular metabolism and, specifically, the regulation of gene expression. Consequently, the number of proposed roles played by G4s in different aspects of gene regulation is constantly increasing. The interest in structural and functional studies of G4s is further increasing due to their potential role in the pathogenesis of human diseases and as novel therapeutic targets.

This Special Issue intends to bring together specialists to cover different aspects of the biology of DNA and RNA G4s. We welcome both original papers and up-to-date reviews that cover topics including but not limited to:

  • Principles of assembly and disassembly of G4s, G4 interactions with ligands;
  • Structural aspects of G4s, structural roles of individual G4-binding proteins and their structural domains;
  • Molecular mechanisms underlying the participation of G4s in gene regulation from DNA replication and recombination to RNA translation, decay, and localization;
  • Interconnection between G4-mediated processes, principles of their regulation;
  • Global-scale analysis of G4s, molecular mechanisms, and functional consequences of their assembly into supramolecular complexes;
  • Connection of G4s to human diseases.

Keywords

  • non-canonical nucleic acid structures
  • G-quadruplexes
  • gene expression
  • G-quadruplex ligands
  • diseases
  • therapeutics

Published Papers (6 papers)

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Research

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Article
Probing GFP Chromophore Analogs as Anti-HIV Agents Targeting LTR-III G-Quadruplex
Biomolecules 2021, 11(10), 1409; https://doi.org/10.3390/biom11101409 - 26 Sep 2021
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Abstract
Green fluorescent protein (GFP) chromophore and its congeners draw significant attention mostly for bioimaging purposes. In this work we probed these compounds as antiviral agents. We have chosen LTR-III DNA G4, the major G-quadruplex (G4) present in the long terminal repeat (LTR) promoter [...] Read more.
Green fluorescent protein (GFP) chromophore and its congeners draw significant attention mostly for bioimaging purposes. In this work we probed these compounds as antiviral agents. We have chosen LTR-III DNA G4, the major G-quadruplex (G4) present in the long terminal repeat (LTR) promoter region of the human immunodeficiency virus-1 (HIV-1), as the target for primary screening and designing antiviral drug candidates. The stabilization of this G4 was previously shown to suppress viral gene expression and replication. FRET-based high-throughput screening (HTS) of 449 GFP chromophore-like compounds revealed a number of hits, sharing some general structural features. Structure-activity relationships (SAR) for the most effective stabilizers allowed us to establish structural fragments, important for G4 binding. Synthetic compounds, developed on the basis of SAR analysis, exhibited high LTR-III G4 stabilization level. NMR spectroscopy and molecular modeling revealed the possible formation of LTR-III G4-ligand complex with one of the lead selective derivative ZS260.1 positioned within the cavity, thus supporting the LTR-III G4 attractiveness for drug targeting. Selected compounds showed moderate activity against HIV-I (EC50 1.78–7.7 μM) in vitro, but the activity was accompanied by pronounced cytotoxicity. Full article
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Article
Recognition Interface of the Thrombin Binding Aptamer Requires Antiparallel Topology of the Quadruplex Core
Biomolecules 2021, 11(9), 1332; https://doi.org/10.3390/biom11091332 - 09 Sep 2021
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Abstract
Recent advances in G-quadruplex (GQ) studies have provided evidence for their important role in key biological processes (replication, transcription, genome stability, and epigenetics). These findings imply highly specific interactions between GQ structures and cellular proteins. The details of the interaction between GQs and [...] Read more.
Recent advances in G-quadruplex (GQ) studies have provided evidence for their important role in key biological processes (replication, transcription, genome stability, and epigenetics). These findings imply highly specific interactions between GQ structures and cellular proteins. The details of the interaction between GQs and cellular proteins remain unknown. It is now accepted that GQ loop elements play a major role in protein recognition. It remains unclear whether and to what extent the GQ core contributes to maintaining the recognition interface. In the current paper, we used the thrombin binding aptamer as a model to study the effect of modification in the quadruplex core on the ability of aptamer to interact with thrombin. We used alpha-2′-deoxyguanosine and 8-bromo-2′-deoxyguanosine to reconfigure the core or to affect synanti preferences of selected dG-residues. Our data suggest that core guanines not only support a particular type of GQ architecture, but also set structural parameters that make GQ protein recognition sensitive to quadruplex topology. Full article
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Article
Impact of a Single Nucleotide Change or Non-Nucleoside Modifications in G-Rich Region on the Quadruplex–Duplex Hybrid Formation
Biomolecules 2021, 11(8), 1236; https://doi.org/10.3390/biom11081236 - 18 Aug 2021
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Abstract
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 [...] Read more.
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. Full article
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Review

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Review
G-Quadruplex-Binding Proteins: Promising Targets for Drug Design
Biomolecules 2022, 12(5), 648; https://doi.org/10.3390/biom12050648 - 29 Apr 2022
Viewed by 374
Abstract
G-quadruplexes (G4s) are non-canonical secondary nucleic acid structures. Sequences with the potential to form G4s are abundant in regulatory regions of the genome including telomeres, promoters and 5′ non-coding regions, indicating they fulfill important genome regulatory functions. Generally, G4s perform various biological functions [...] Read more.
G-quadruplexes (G4s) are non-canonical secondary nucleic acid structures. Sequences with the potential to form G4s are abundant in regulatory regions of the genome including telomeres, promoters and 5′ non-coding regions, indicating they fulfill important genome regulatory functions. Generally, G4s perform various biological functions by interacting with proteins. In recent years, an increasing number of G-quadruplex-binding proteins have been identified with biochemical experiments. G4-binding proteins are involved in vital cellular processes such as telomere maintenance, DNA replication, gene transcription, mRNA processing. Therefore, G4-binding proteins are also associated with various human diseases. An intensive study of G4-protein interactions provides an attractive approach for potential therapeutics and these proteins can be considered as drug targets for novel medical treatment. In this review, we present biological functions and structural properties of G4-binding proteins, and discuss how to exploit G4-protein interactions to develop new therapeutic targets. Full article
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Review
Reversal of G-Quadruplexes’ Role in Translation Control When Present in the Context of an IRES
Biomolecules 2022, 12(2), 314; https://doi.org/10.3390/biom12020314 - 16 Feb 2022
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Abstract
G-quadruplexes (GQs) are secondary nucleic acid structures that play regulatory roles in various cellular processes. G-quadruplex-forming sequences present within the 5′ UTR of mRNAs can function not only as repressors of translation but also as elements required for optimum function. Based upon previous [...] Read more.
G-quadruplexes (GQs) are secondary nucleic acid structures that play regulatory roles in various cellular processes. G-quadruplex-forming sequences present within the 5′ UTR of mRNAs can function not only as repressors of translation but also as elements required for optimum function. Based upon previous reports, the majority of the 5′ UTR GQ structures inhibit translation, presumably by blocking the ribosome scanning process that is essential for detection of the initiation codon. However, there are certain mRNAs containing GQs that have been identified as positive regulators of translation, as they are needed for translation initiation. While most cellular mRNAs utilize the 5′ cap structure to undergo cap-dependent translation initiation, many rely on cap-independent translation under certain conditions in which the cap-dependent initiation mechanism is not viable or slowed down, for example, during development, under stress and in many diseases. Cap-independent translation mainly occurs via Internal Ribosomal Entry Sites (IRESs) that are located in the 5′ UTR of mRNAs and are equipped with structural features that can recruit the ribosome or other factors to initiate translation without the need for a 5′ cap. In this review, we will focus only on the role of RNA GQs present in the 5′ UTR of mRNAs, where they play a critical role in translation initiation, and discuss the potential mechanism of this phenomenon, which is yet to be fully delineated. Full article
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Review
Impact of G-Quadruplexes on the Regulation of Genome Integrity, DNA Damage and Repair
Biomolecules 2021, 11(9), 1284; https://doi.org/10.3390/biom11091284 - 27 Aug 2021
Cited by 4 | Viewed by 1040
Abstract
DNA G-quadruplexes (G4s) are known to be an integral part of the complex regulatory systems in both normal and pathological cells. At the same time, the ability of G4s to impede DNA replication plays a critical role in genome integrity. This review summarizes [...] Read more.
DNA G-quadruplexes (G4s) are known to be an integral part of the complex regulatory systems in both normal and pathological cells. At the same time, the ability of G4s to impede DNA replication plays a critical role in genome integrity. This review summarizes the results of recent studies of G4-mediated genomic and epigenomic instability, together with associated DNA damage and repair processes. Although the underlying mechanisms remain to be elucidated, it is known that, among the proteins that recognize G4 structures, many are linked to DNA repair. We analyzed the possible role of G4s in promoting double-strand DNA breaks, one of the most deleterious DNA lesions, and their repair via error-prone mechanisms. The patterns of G4 damage, with a focus on the introduction of oxidative guanine lesions, as well as their removal from G4 structures by canonical repair pathways, were also discussed together with the effects of G4s on the repair machinery. According to recent findings, there must be a delicate balance between G4-induced genome instability and G4-promoted repair processes. A broad overview of the factors that modulate the stability of G4 structures in vitro and in vivo is also provided here. Full article
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