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G-quadruplex and Microorganisms

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 58275

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Prof. Dr. Sara N. Richter

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Department of Molecular Medicine, University of Padua, Padua, Italy
Interests: non-canonical nucleic acid structures; G-quadruplex; i-motifs; viruses; HIV-1; HSV-1; microorganisms; cancer; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

G-quadruplexes (G4s) are nucleic acid secondary structures that form in DNA or RNA guanine (G)-rich strands. Four G residues are connected through Hoogsteen-type hydrogen bonds, forming a G-tetrad and two or more G-tetrads can stack on top of each other forming the G4, which is stabilized by coordinating monovalent cations, such as K⁺.

G4s have been extensively described in the human genome, especially in telomeres and oncogene promoters, where their involvement in the regulation of different biological pathways such as replication, transcription, translation and genome instability has been suggested. In addition to humans, putative G4-forming sequences have been found in other mammalian genomes, plants, yeasts, protozoa, bacteria and viruses. In particular, in the recent years, the presence of G4s in microorganisms has attracted increasing interest. In prokaryotes G4 sequences have been found in several human pathogens and bacterial species present in the environment. Bacterial enzymes able to process G4s have also been identified. In viruses, G4s are involved in key steps of the viral life cycle: they been associated with pathogenic mechanisms of the human immunodeficiency virus (HIV), herpes simplex virus 1 (HSV-1), the human papilloma, Zika, Ebola, hepatitis C virus and several other virus genomes. G4 binding proteins and mRNA G4s have been implicated in the regulation of the viral genome replication and translation. G4 ligands have been developed and tested both as tools to study the complexity of G4-mediated mechanisms in the viral life cycle, and as therapeutic agents. Moreover, oligonucleotides that fold into G4 have been found to be active against several microorganisms. This Special Issue will focus on G4s involved in microorganisms addressing all the above aspects.

Prof. Sara N. Richter
Guest Editor

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Keywords

G-quadruplex
viruses
bacteria
protozoa
microorganisms
aptamers
G-quadruplex ligands
infections
anti-infective agents
nucleic acids conformation

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Published Papers (11 papers)

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18 pages, 2379 KiB

Open AccessArticle

Conserved G-Quadruplexes Regulate the Immediate Early Promoters of Human Alphaherpesviruses

by Ilaria Frasson, Matteo Nadai and Sara N. Richter

Molecules 2019, 24(13), 2375; https://doi.org/10.3390/molecules24132375 - 27 Jun 2019

Cited by 37 | Viewed by 4811

Abstract

Human Alphaherpesviruses comprise three members, herpes simplex virus (HSV) 1 and 2 and varicella zoster virus (VZV). These viruses are characterized by a lytic cycle in epithelial cells and latency in the nervous system, with lifelong infections that may periodically reactivate and lead to serious complications, especially in immunocompromised patients. The mechanisms that regulate viral transcription have not been fully elucidated, but the master role of the immediate early (IE) genes has been established. G-quadruplexes are non-canonical nucleic-acid structures that control transcription, replication, and recombination in many organisms including viruses and that represent attractive antiviral targets. In this work, we investigate the presence, conservation, folding and activity of G-quadruplexes in the IE promoters of the Alphaherpesviruses. Our analysis shows that all IE promoters in the genome of HSV-1, HSV-2 and VZV contain fully conserved G-quadruplex forming sequences. These comprise sequences with long loops and bulges, and thus deviating from the classic G-quadruplex motifs. Moreover, their location is both on the leading and lagging strand and in some instances they contain exuberant G-tracts. Biophysical and biological analysis proved that all sequences actually fold into G-quadruplex under physiological conditions and can be further stabilized by the G-quadruplex ligand BRACO-19, with subsequent impairment of viral IE gene transcription in cells. These results help shed light on the control of viral transcription and indicate new viral targets to design drugs that impair the early steps of Alphaherpesviruses. In addition, they validate the significance of G-quadruplexes in the general regulation of viral cycles. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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21 pages, 5554 KiB

Open AccessArticle

Bulged and Canonical G-Quadruplex Conformations Determine NDPK Binding Specificity

by Mykhailo Kopylov, Trevia M. Jackson and M. Elizabeth Stroupe

Molecules 2019, 24(10), 1988; https://doi.org/10.3390/molecules24101988 - 23 May 2019

Cited by 4 | Viewed by 3765

Abstract

Guanine-rich DNA strands can adopt tertiary structures known as G-quadruplexes (G4s) that form when Hoogsteen base-paired guanines assemble as planar stacks, stabilized by a central cation like K⁺. In this study, we investigated the conformational heterogeneity of a G-rich sequence from the 5′ untranslated region of the Zea mays hexokinase4 gene. This sequence adopted an extensively polymorphic G-quadruplex, including non-canonical bulged G-quadruplex folds that co-existed in solution. The nature of this polymorphism depended, in part, on the incorporation of different sets of adjacent guanines into a quadruplex core, which permitted the formation of the different conformations. Additionally, we showed that the maize homolog of the human nucleoside diphosphate kinase (NDPK) NM23-H2 protein—ZmNDPK1—specifically recognizes and promotes formation of a subset of these conformations. Heteromorphic G-quadruplexes play a role in microorganisms’ ability to evade the host immune system, so we also discuss how the underlying properties that determine heterogeneity of this sequence could apply to microorganism G4s. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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17 pages, 4331 KiB

Open AccessArticle

Relationship Between G-Quadruplex Sequence Composition in Viruses and Their Hosts

by Emilia Puig Lombardi, Arturo Londoño-Vallejo and Alain Nicolas

Molecules 2019, 24(10), 1942; https://doi.org/10.3390/molecules24101942 - 20 May 2019

Cited by 15 | Viewed by 3806

Abstract

A subset of guanine-rich nucleic acid sequences has the potential to fold into G-quadruplex (G4) secondary structures, which are functionally important for several biological processes, including genome stability and regulation of gene expression. Putative quadruplex sequences (PQSs) G₃₊N_1–7G₃₊N_1–7G₃₊N_1–7G₃₊ are widely found in eukaryotic and prokaryotic genomes, but the base composition of the N_1-7 loops is biased across species. Since the viruses partially hijack their hosts’ cellular machinery for proliferation, we examined the PQS motif size, loop length, and nucleotide compositions of 7370 viral genome assemblies and compared viral and host PQS motifs. We studied seven viral taxa infecting five distant eukaryotic hosts and created a resource providing a comprehensive view of the viral quadruplex motifs. Overall, short-looped PQSs are predominant and with a similar composition across viral taxonomic groups, albeit subtle trends emerge upon classification by hosts. Specifically, there is a higher frequency of pyrimidine loops in viruses infecting animals irrespective of the viruses’ genome type. This observation is confirmed by an in-depth analysis of the Herpesviridae family of viruses, which showed a distinctive accumulation of thermally stable C-looped quadruplexes in viruses infecting high-order vertebrates. The occurrence of viral C-looped G4s, which carry binding sites for host transcription factors, as well as the high prevalence of viral TTA-looped G4s, which are identical to vertebrate telomeric motifs, provide concrete examples of how PQSs may help viruses impinge upon, and benefit from, host functions. More generally, these observations suggest a co-evolution of virus and host PQSs, thus underscoring the potential functional significance of G4s. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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15 pages, 2602 KiB

Open AccessArticle

A Novel G-Quadruplex Binding Protein in Yeast—Slx9

by Silvia Götz, Satyaprakash Pandey, Sabrina Bartsch, Stefan Juranek and Katrin Paeschke

Molecules 2019, 24(9), 1774; https://doi.org/10.3390/molecules24091774 - 7 May 2019

Cited by 13 | Viewed by 4401

Abstract

G-quadruplex (G4) structures are highly stable four-stranded DNA and RNA secondary structures held together by non-canonical guanine base pairs. G4 sequence motifs are enriched at specific sites in eukaryotic genomes, suggesting regulatory functions of G4 structures during different biological processes. Considering the high thermodynamic stability of G4 structures, various proteins are necessary for G4 structure formation and unwinding. In a yeast one-hybrid screen, we identified Slx9 as a novel G4-binding protein. We confirmed that Slx9 binds to G4 DNA structures in vitro. Despite these findings, Slx9 binds only insignificantly to G-rich/G4 regions in Saccharomyces cerevisiae as demonstrated by genome-wide ChIP-seq analysis. However, Slx9 binding to G4s is significantly increased in the absence of Sgs1, a RecQ helicase that regulates G4 structures. Different genetic and molecular analyses allowed us to propose a model in which Slx9 recognizes and protects stabilized G4 structures in vivo. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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13 pages, 2437 KiB

Open AccessArticle

The Presence and Localization of G-Quadruplex Forming Sequences in the Domain of Bacteria

by Martin Bartas, Michaela Čutová, Václav Brázda, Patrik Kaura, Jiří Šťastný, Jan Kolomazník, Jan Coufal, Pratik Goswami, Jiří Červeň and Petr Pečinka

Molecules 2019, 24(9), 1711; https://doi.org/10.3390/molecules24091711 - 2 May 2019

Cited by 68 | Viewed by 7841

Abstract

The role of local DNA structures in the regulation of basic cellular processes is an emerging field of research. Amongst local non-B DNA structures, the significance of G-quadruplexes was demonstrated in the last decade, and their presence and functional relevance has been demonstrated in many genomes, including humans. In this study, we analyzed the presence and locations of G-quadruplex-forming sequences by G4Hunter in all complete bacterial genomes available in the NCBI database. G-quadruplex-forming sequences were identified in all species, however the frequency differed significantly across evolutionary groups. The highest frequency of G-quadruplex forming sequences was detected in the subgroup Deinococcus-Thermus, and the lowest frequency in Thermotogae. G-quadruplex forming sequences are non-randomly distributed and are favored in various evolutionary groups. G-quadruplex-forming sequences are enriched in ncRNA segments followed by mRNAs. Analyses of surrounding sequences showed G-quadruplex-forming sequences around tRNA and regulatory sequences. These data point to the unique and non-random localization of G-quadruplex-forming sequences in bacterial genomes. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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14 pages, 1981 KiB

Open AccessArticle

Conformational Dynamics of the RNA G-Quadruplex and its Effect on Translation Efficiency

by Tamaki Endoh and Naoki Sugimoto

Molecules 2019, 24(8), 1613; https://doi.org/10.3390/molecules24081613 - 24 Apr 2019

Cited by 25 | Viewed by 4870

Abstract

During translation, intracellular mRNA folds co-transcriptionally and must refold following the passage of ribosome. The mRNAs can be entrapped in metastable structures during these folding events. In the present study, we evaluated the conformational dynamics of the kinetically favored, metastable, and hairpin-like structure, which disturbs the thermodynamically favored G-quadruplex structure, and its effect on co-transcriptional translation in prokaryotic cells. We found that nascent mRNA forms a metastable hairpin-like structure during co-transcriptional folding instead of the G-quadruplex structure. When the translation progressed co-transcriptionally before the metastable hairpin-like structure transition to the G-quadruplex, function of the G-quadruplex as a roadblock of the ribosome was sequestered. This suggested that kinetically formed RNA structures had a dominant effect on gene expression in prokaryotes. The results of this study indicate that it is critical to consider the conformational dynamics of RNA-folding to understand the contributions of the mRNA structures in controlling gene expression. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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19 pages, 3647 KiB

Open AccessArticle

Towards Understanding of Polymorphism of the G-rich Region of Human Papillomavirus Type 52

by Maja Marušič and Janez Plavec

Molecules 2019, 24(7), 1294; https://doi.org/10.3390/molecules24071294 - 2 Apr 2019

Cited by 22 | Viewed by 3940

Abstract

The potential to affect gene expression via G-quadruplex stabilization has been extended to all domains of life, including viruses. Here, we investigate the polymorphism and structures of G-quadruplexes of the human papillomavirus type 52 with UV, CD and NMR spectroscopy and gel electrophoresis. We show that oligonucleotide with five G-tracts folds into several structures and that naturally occurring single nucleotide polymorphisms (SNPs) have profound effects on the structural polymorphism in the context of G-quadruplex forming propensity, conformational heterogeneity and folding stability. With help of SNP analysis, we were able to select one of the predominant forms, formed by G-rich sequence d(G₃TAG₃CAG₄ACACAG₃T). This oligonucleotide termed HPV52_(1–4) adopts a three G-quartet snap back (3 + 1) type scaffold with four syn guanine residues, two edgewise loops spanning the same groove, a no-residue V loop and a propeller type loop. The first guanine residue is incorporated in the central G-quartet and all four-guanine residues from G4 stretch are included in the three quartet G-quadruplex core. Modification studies identified several structural elements that are important for stabilization of the described G-quadruplex fold. Our results expand set of G-rich targets in viral genomes and address the fundamental questions regarding folding of G-rich sequences. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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23 pages, 5356 KiB

Open AccessArticle

Intensive Distribution of G₂-Quaduplexes in the Pseudorabies Virus Genome and Their Sensitivity to Cations and G-Quadruplex Ligands

by Hui Deng, Bowen Gong, Zhiquan Yang, Zhen Li, Huan Zhou, Yashu Zhang, Xiaohui Niu, Sisi Liu and Dengguo Wei

Molecules 2019, 24(4), 774; https://doi.org/10.3390/molecules24040774 - 21 Feb 2019

Cited by 13 | Viewed by 4960

Abstract

Guanine-rich sequences in the genomes of herpesviruses can fold into G-quadruplexes. Compared with the widely-studied G₃-quadruplexes, the dynamic G₂-quadruplexes are more sensitive to the cell microenvironment, but they attract less attention. Pseudorabies virus (PRV) is the model species for the study of the latency and reactivation of herpesvirus in the nervous system. A total of 1722 G₂-PQSs and 205 G₃-PQSs without overlap were identified in the PRV genome. Twelve G₂-PQSs from the CDS region exhibited high conservation in the genomes of the Varicellovirus genus. Eleven G₂-PQSs were 100% conserved in the repeated region of the annotated PRV genomes. There were 212 non-redundant G₂-PQSs in the 3′ UTR and 19 non-redundant G₂-PQSs in the 5′ UTR, which would mediate gene expression in the post-transcription and translation processes. The majority of examined G₂-PQSs formed parallel structures and exhibited different sensitivities to cations and small molecules in vitro. Two G₂-PQSs, respectively, from 3′ UTR of UL5 (encoding helicase motif) and UL9 (encoding sequence-specific ori-binding protein) exhibited diverse regulatory activities with/without specific ligands in vivo. The G-quadruplex ligand, NMM, exhibited a potential for reducing the virulence of the PRV Ea strain. The systematic analysis of the distribution of G₂-PQSs in the PRV genomes could guide further studies of the G-quadruplexes’ functions in the life cycle of herpesviruses. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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11 pages, 2503 KiB

Open AccessCommunication

In Cellulo Protein-mRNA Interaction Assay to Determine the Action of G-Quadruplex-Binding Molecules

by Rodrigo Prado Martins, Sarah Findakly, Chrysoula Daskalogianni, Marie-Paule Teulade-Fichou, Marc Blondel and Robin Fåhraeus

Molecules 2018, 23(12), 3124; https://doi.org/10.3390/molecules23123124 - 29 Nov 2018

Cited by 19 | Viewed by 5588

Abstract

Protein-RNA interactions (PRIs) control pivotal steps in RNA biogenesis, regulate multiple physiological and pathological cellular networks, and are emerging as important drug targets. However, targeting of specific protein-RNA interactions for therapeutic developments is still poorly advanced. Studies and manipulation of these interactions are technically challenging and in vitro drug screening assays are often hampered due to the complexity of RNA structures. The binding of nucleolin (NCL) to a G-quadruplex (G4) structure in the messenger RNA (mRNA) of the Epstein-Barr virus (EBV)-encoded EBNA1 has emerged as an interesting therapeutic target to interfere with immune evasion of EBV-associated cancers. Using the NCL-EBNA1 mRNA interaction as a model, we describe a quantitative proximity ligation assay (PLA)-based in cellulo approach to determine the structure activity relationship of small chemical G4 ligands. Our results show how different G4 ligands have different effects on NCL binding to G4 of the EBNA1 mRNA and highlight the importance of in-cellulo screening assays for targeting RNA structure-dependent interactions. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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Review

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34 pages, 6409 KiB

Open AccessReview

G-Quadruplex-Based Fluorescent Turn-On Ligands and Aptamers: From Development to Applications

by Mubarak I. Umar, Danyang Ji, Chun-Yin Chan and Chun Kit Kwok

Molecules 2019, 24(13), 2416; https://doi.org/10.3390/molecules24132416 - 30 Jun 2019

Cited by 66 | Viewed by 8511

Abstract

Guanine (G)-quadruplexes (G4s) are unique nucleic acid structures that are formed by stacked G-tetrads in G-rich DNA or RNA sequences. G4s have been reported to play significant roles in various cellular events in both macro- and micro-organisms. The identification and characterization of G4s can help to understand their different biological roles and potential applications in diagnosis and therapy. In addition to biophysical and biochemical methods to interrogate G4 formation, G4 fluorescent turn-on ligands can be used to target and visualize G4 formation both in vitro and in cells. Here, we review several representative classes of G4 fluorescent turn-on ligands in terms of their interaction mechanism and application perspectives. Interestingly, G4 structures are commonly identified in DNA and RNA aptamers against targets that include proteins and small molecules, which can be utilized as G4 tools for diverse applications. We therefore also summarize the recent development of G4-containing aptamers and highlight their applications in biosensing, bioimaging, and therapy. Moreover, we discuss the current challenges and future perspectives of G4 fluorescent turn-on ligands and G4-containing aptamers. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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11 pages, 817 KiB

Open AccessReview

Parasitic Protozoa: Unusual Roles for G-Quadruplexes in Early-Diverging Eukaryotes

by Franck Dumetz and Catherine J. Merrick

Molecules 2019, 24(7), 1339; https://doi.org/10.3390/molecules24071339 - 5 Apr 2019

Cited by 17 | Viewed by 4681

Abstract

Guanine-quadruplex (G4) motifs, at both the DNA and RNA levels, have assumed an important place in our understanding of the biology of eukaryotes, bacteria and viruses. However, it is generally little known that their very first description, as well as the foundational work on G4s, was performed on protozoans: unicellular life forms that are often parasitic. In this review, we provide a historical perspective on the discovery of G4s, intertwined with their biological significance across the protozoan kingdom. This is a history in three parts: first, a period of discovery including the first characterisation of a G4 motif at the DNA level in ciliates (environmental protozoa); second, a period less dense in publications concerning protozoa, during which DNA G4s were discovered in both humans and viruses; and third, a period of renewed interest in protozoa, including more mechanistic work in ciliates but also in pathogenic protozoa. This last period has opened an exciting prospect of finding new anti-parasitic drugs to interfere with parasite biology, thus adding new compounds to the therapeutic arsenal. Full article

(This article belongs to the Special Issue G-quadruplex and Microorganisms)

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