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Investigation of the Importance of Non-B DNA Structures at the...
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Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (10 December 2022) | Viewed by 21252

Special Issue Editors

Dr. Emanuela Ruggiero

E-Mail Website
Guest Editor
Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
Interests: G-quadruplex; i-motif; viruses; cancer; targeting
Dr. Marco Di Antonio

E-Mail Website
Guest Editor
1. Department of Chemistry, MSRH, Imperial College London, London SW12 0BX, UK
2. The Francis Crick Institute, London NW1 1AT, UK
Interests: G-quadruplex; epigenetics; transcription; aging; chemical-biology
Dr. Samantha Kendrick

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Interests: G-quadruplex; i-motif; lymphoma; targeting; transcription

Special Issue Information

Dear Colleagues,

DNA is a very polymorphic macromolecule, the folding of which extends far beyond the double helix. This dynamic nature of DNA leads to the formation of transient alternative structures that regulate crucial cellular mechanisms, thus affecting the cell life cycle. Sequences with high propensity to form non-canonical structures are particularly enriched in disease-related human genes, as well as in the genome of various microorganisms. This observation suggests a potential role of non-B DNA in the onset of several human diseases, including cancer, neurodegenerative disorders, and infectious diseases. Recent studies addressing the role of DNA secondary structures have mainly focused on tetraplex structures, such as G-quadruplexes and i-motifs, corroborating the potential of these structures as innovative targets for therapeutic intervention. Nonetheless, interesting evidence also hints at a potential biological role for triplexes, hairpins, and cruciform structures. Consequently, interest in studying non-canonical DNA structures has significantly expanded in recent years, engaging research spanning from synthetic chemistry to cell biology. This Special Issue aims to gather experts in the field of non-B DNA to cover different facets of non-canonical nucleic acid structures and recent advances in this area at the interface between chemistry and biology. We welcome both original papers and up-to-date reviews that cover topics including, but not limited to:

  • Characterization, visualization, and targeting of non-B DNA;
  • Non-canonical DNA interacting proteins;
  • Alternative DNA structures in gene regulation;
  • Biological role of non-B DNA in human diseases.

Dr. Emanuela Ruggiero
Dr. Marco Di Antonio
Dr. Samantha Kendrick
Guest Editors

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Keywords

  • G-quaduplexes
  • I-motifs
  • non-B DNA
  • gene regulation
  • epigenetics
  • DNA targeting
  • chromatin organization
  • DNA replication

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Published Papers (7 papers)

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Research

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23 pages, 4508 KiB  
Article
MOSR and NDHA Genes Comprising G-Quadruplex as Promising Therapeutic Targets against Mycobacterium tuberculosis: Molecular Recognition by Mitoxantrone Suppresses Replication and Gene Regulation
by Arpita Dey, Kushi Anand, Amit Singh, Ramasare Prasad and Ritu Barthwal
Genes 2023, 14(5), 978; https://doi.org/10.3390/genes14050978 - 26 Apr 2023
Cited by 5 | Viewed by 2115
Abstract
Occurrence of non-canonical G-quadruplex (G4) DNA structures in the genome have been recognized as key factors in gene regulation and several other cellular processes. The mosR and ndhA genes involved in pathways of oxidation sensing regulation and ATP generation, respectively, make Mycobacterium tuberculosis [...] Read more.
Occurrence of non-canonical G-quadruplex (G4) DNA structures in the genome have been recognized as key factors in gene regulation and several other cellular processes. The mosR and ndhA genes involved in pathways of oxidation sensing regulation and ATP generation, respectively, make Mycobacterium tuberculosis (Mtb) bacteria responsible for oxidative stress inside host macrophage cells. Circular Dichroism spectra demonstrate stable hybrid G4 DNA conformations of mosR/ndhA DNA sequences. Real-time binding of mitoxantrone to G4 DNA with an affinity constant ~105–107 M−1, leads to hypochromism with a red shift of ~18 nm, followed by hyperchromism in the absorption spectra. The corresponding fluorescence is quenched with a red shift ~15 nm followed by an increase in intensity. A change in conformation of the G4 DNA accompanies the formation of multiple stoichiometric complexes with a dual binding mode. The external binding of mitoxantrone with a partial stacking with G-quartets and/or groove binding induces significant thermal stabilization, ~20–29 °C in ndhA/mosR G4 DNA. The interaction leads to a two/four-fold downregulation of transcriptomes of mosR/ndhA genes apart from the suppression of DNA replication by Taq polymerase enzyme, establishing the role of mitoxantrone in targeting G4 DNA, as an alternate strategy for effective anti-tuberculosis action in view of deadly multi-drug resistant tuberculosis disease causing bacterial strains t that arise from existing therapeutic treatments. Full article
(This article belongs to the Special Issue Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology)
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11 pages, 1151 KiB  
Article
Genomic Analysis of Non-B Nucleic Acids Structures in SARS-CoV-2: Potential Key Roles for These Structures in Mutability, Translation, and Replication?
by Stefan Bidula and Václav Brázda
Genes 2023, 14(1), 157; https://doi.org/10.3390/genes14010157 - 6 Jan 2023
Cited by 3 | Viewed by 2247
Abstract
Non-B nucleic acids structures have arisen as key contributors to genetic variation in SARS-CoV-2. Herein, we investigated the presence of defining spike protein mutations falling within inverted repeats (IRs) for 18 SARS-CoV-2 variants, discussed the potential roles of G-quadruplexes (G4s) in SARS-CoV-2 biology, [...] Read more.
Non-B nucleic acids structures have arisen as key contributors to genetic variation in SARS-CoV-2. Herein, we investigated the presence of defining spike protein mutations falling within inverted repeats (IRs) for 18 SARS-CoV-2 variants, discussed the potential roles of G-quadruplexes (G4s) in SARS-CoV-2 biology, and identified potential pseudoknots within the SARS-CoV-2 genome. Surprisingly, there was a large variation in the number of defining spike protein mutations arising within IRs between variants and these were more likely to occur in the stem region of the predicted hairpin stem-loop secondary structure. Notably, mutations implicated in ACE2 binding and propagation (e.g., ΔH69/V70, N501Y, and D614G) were likely to occur within IRs, whilst mutations involved in antibody neutralization and reduced vaccine efficacy (e.g., T19R, ΔE156, ΔF157, R158G, and G446S) were rarely found within IRs. We also predicted that RNA pseudoknots could predominantly be found within, or next to, 29 mutations found in the SARS-CoV-2 spike protein. Finally, the Omicron variants BA.2, BA.4, BA.5, BA.2.12.1, and BA.2.75 appear to have lost two of the predicted G4-forming sequences found in other variants. These were found in nsp2 and the sequence complementary to the conserved stem-loop II-like motif (S2M) in the 3′ untranslated region (UTR). Taken together, non-B nucleic acids structures likely play an integral role in SARS-CoV-2 evolution and genetic diversity. Full article
(This article belongs to the Special Issue Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology)
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11 pages, 1743 KiB  
Article
G-quadruplexes Mark Sites of Methylation Instability Associated with Ageing and Cancer
by Jonas Rauchhaus, Jenna Robinson, Ludovica Monti and Marco Di Antonio
Genes 2022, 13(9), 1665; https://doi.org/10.3390/genes13091665 - 17 Sep 2022
Cited by 6 | Viewed by 3840
Abstract
Regulation of the epigenome is critical for healthy cell function but can become disrupted with age, leading to aberrant epigenetic profiles including altered DNA methylation. Recent studies have indicated that DNA methylation homeostasis can be compromised by the formation of DNA secondary structures [...] Read more.
Regulation of the epigenome is critical for healthy cell function but can become disrupted with age, leading to aberrant epigenetic profiles including altered DNA methylation. Recent studies have indicated that DNA methylation homeostasis can be compromised by the formation of DNA secondary structures known as G-quadruplexes (G4s), which form in guanine-rich regions of the genome. G4s can be recognised and bound by certain methylation-regulating enzymes, and in turn perturb the surrounding methylation architecture. However, the effect G4 formation has on DNA methylation at critical epigenetic sites remains elusive and poorly explored. In this work, we investigate the association between G4 sequences and prominent DNA methylation sites, termed ‘ageing clocks’, that act as bona fide dysregulated regions in aged and cancerous cells. Using a combination of in vitro (G4-seq) and in cellulo (BG4-ChIP) G4 distribution maps, we show that ageing clocks sites are significantly enriched with G4-forming sequences. The observed enrichment also varies across species and cell lines, being least significant in healthy cells and more pronounced in tumorigenic cells. Overall, our results suggest a biological significance of G4s in the realm of DNA methylation, which may be important for further deciphering the driving forces of diseases characterised by epigenetic abnormality, including ageing. Full article
(This article belongs to the Special Issue Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology)
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17 pages, 1625 KiB  
Article
Indoloquinoline-Mediated Targeted Downregulation of KRAS through Selective Stabilization of the Mid-Promoter G-Quadruplex Structure
by Alexandra Maria Psaras, Rhianna K. Carty, Jared T. Miller, L. Nathan Tumey and Tracy A. Brooks
Genes 2022, 13(8), 1440; https://doi.org/10.3390/genes13081440 - 13 Aug 2022
Cited by 4 | Viewed by 2390
Abstract
KRAS is a well-validated anti-cancer therapeutic target, whose transcriptional downregulation has been demonstrated to be lethal to tumor cells with aberrant KRAS signaling. G-quadruplexes (G4s) are non-canonical nucleic acid structures that mediate central dogmatic events, such as DNA repair, telomere elongation, transcription and [...] Read more.
KRAS is a well-validated anti-cancer therapeutic target, whose transcriptional downregulation has been demonstrated to be lethal to tumor cells with aberrant KRAS signaling. G-quadruplexes (G4s) are non-canonical nucleic acid structures that mediate central dogmatic events, such as DNA repair, telomere elongation, transcription and splicing events. G4s are attractive drug targets, as they are more globular than B-DNA, enabling more selective gene interactions. Moreover, their genomic prevalence is increased in oncogenic promoters, their formation is increased in human cancers, and they can be modulated with small molecules or targeted nucleic acids. The putative formation of multiple G4s has been described in the literature, but compounds with selectivity among these structures have not yet been able to distinguish between the biological contribution of the predominant structures. Using cell free screening techniques, synthesis of novel indoloquinoline compounds and cellular models of KRAS-dependent cancer cells, we describe compounds that choose between KRAS promoter G4near and G4mid, correlate compound cytotoxic activity with KRAS regulation, and highlight G4mid as the lead molecular non-canonical structure for further targeting efforts. Full article
(This article belongs to the Special Issue Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology)
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20 pages, 5210 KiB  
Article
Targeting a Novel G-Quadruplex in the CARD11 Oncogene Promoter with Naptho(2,1-b)furan-1-ethanol,2-nitro- Requires the Nitro Group
by Kennith Swafford, Baku Acharya, Ying-Zhi Xu, Thomas Raney, Mason McCrury, Debasmita Saha, Brendan Frett and Samantha Kendrick
Genes 2022, 13(7), 1144; https://doi.org/10.3390/genes13071144 - 25 Jun 2022
Cited by 2 | Viewed by 2559
Abstract
The aggressive nature of the activated B cell such as (ABC) subtype of diffuse large B cell (DLBCL) is frequently associated with altered B cell Receptor (BCR) signaling through the activation of key components including the scaffolding protein, CARD11. Most inhibitors, such [...] Read more.
The aggressive nature of the activated B cell such as (ABC) subtype of diffuse large B cell (DLBCL) is frequently associated with altered B cell Receptor (BCR) signaling through the activation of key components including the scaffolding protein, CARD11. Most inhibitors, such as ibrutinib, target downstream BCR kinases with often modest and temporary responses for DLBCL patients. Here, we pursue an alternative strategy to target the BCR pathway by leveraging a novel DNA secondary structure to repress transcription. We discovered that a highly guanine (G)-rich element within the CARD11 promoter forms a stable G-quadruplex (G4) using circular dichroism and polymerase stop biophysical techniques. We then identified a small molecule, naptho(2,1-b)furan-1-ethanol,2-nitro- (NSC373981), from a fluorescence-resonance energy transfer-based screen that stabilized CARD11 G4 and inhibited CARD11 transcription in DLBCL cells. In generating and testing analogs of NSC373981, we determined that the nitro group is likely essential for the downregulation of CARD11 and interaction with CARD11 G4, and the removal of the ethanol side chain enhanced this activity. Of note, the expression of BCL2 and MYC, two other key oncogenes in DLBCL pathology with known promoter G4 structures, were often concurrently repressed with NSC373981 and the highly potent R158 analog. Our findings highlight a novel approach to treat aggressive DLBCL by silencing CARD11 gene expression that warrants further investigation. Full article
(This article belongs to the Special Issue Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology)
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Review

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16 pages, 2386 KiB  
Review
G-Quadruplexes in Nuclear Biomolecular Condensates
by Iuliia Pavlova, Mikhail Iudin, Anastasiya Surdina, Vjacheslav Severov and Anna Varizhuk
Genes 2023, 14(5), 1076; https://doi.org/10.3390/genes14051076 - 13 May 2023
Cited by 7 | Viewed by 3323
Abstract
G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation of related proteins into liquid condensates on DNA/RNA matrices. While cytoplasmic G4s are acknowledged scaffolds of potentially pathogenic condensates, [...] Read more.
G-quadruplexes (G4s) have long been implicated in the regulation of chromatin packaging and gene expression. These processes require or are accelerated by the separation of related proteins into liquid condensates on DNA/RNA matrices. While cytoplasmic G4s are acknowledged scaffolds of potentially pathogenic condensates, the possible contribution of G4s to phase transitions in the nucleus has only recently come to light. In this review, we summarize the growing evidence for the G4-dependent assembly of biomolecular condensates at telomeres and transcription initiation sites, as well as nucleoli, speckles, and paraspeckles. The limitations of the underlying assays and the remaining open questions are outlined. We also discuss the molecular basis for the apparent permissive role of G4s in the in vitro condensate assembly based on the interactome data. To highlight the prospects and risks of G4-targeting therapies with respect to the phase transitions, we also touch upon the reported effects of G4-stabilizing small molecules on nuclear biomolecular condensates. Full article
(This article belongs to the Special Issue Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology)
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20 pages, 2358 KiB  
Review
Alternative RNA Conformations: Companion or Combatant
by Payal Gupta, Rushikesh M. Khadake, Shounok Panja, Krushna Shinde and Ambadas B. Rode
Genes 2022, 13(11), 1930; https://doi.org/10.3390/genes13111930 - 23 Oct 2022
Cited by 8 | Viewed by 3549
Abstract
RNA molecules, in one form or another, are involved in almost all aspects of cell physiology, as well as in disease development. The diversity of the functional roles of RNA comes from its intrinsic ability to adopt complex secondary and tertiary structures, rivaling [...] Read more.
RNA molecules, in one form or another, are involved in almost all aspects of cell physiology, as well as in disease development. The diversity of the functional roles of RNA comes from its intrinsic ability to adopt complex secondary and tertiary structures, rivaling the diversity of proteins. The RNA molecules form dynamic ensembles of many interconverting conformations at a timescale of seconds, which is a key for understanding how they execute their cellular functions. Given the crucial role of RNAs in various cellular processes, we need to understand the RNA molecules from a structural perspective. Central to this review are studies aimed at revealing the regulatory role of conformational equilibria in RNA in humans to understand genetic diseases such as cancer and neurodegenerative diseases, as well as in pathogens such as bacteria and viruses so as to understand the progression of infectious diseases. Furthermore, we also summarize the prior studies on the use of RNA structures as platforms for the rational design of small molecules for therapeutic applications. Full article
(This article belongs to the Special Issue Investigation of the Importance of Non-B DNA Structures at the Interface between Chemistry and Biology)
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