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Special Issue "G-quadruplex and Microorganisms"

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

Deadline for manuscript submissions: 31 May 2019

Special Issue Editor

Guest Editor
Prof. Sara N. Richter

Department of Molecular Medicine, University of Padua, Padua, Italy
Website | E-Mail
Interests: G-quadruplex; nucleic acids conformation; G-quadruplex ligands; aptamers; microorganisms; viruses; bacteria; protozoa; infections; anti-infective agents

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

Published Papers (9 papers)

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Research

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Open AccessArticle
Bulged and Canonical G-Quadruplex Conformations Determine NDPK Binding Specificity
Molecules 2019, 24(10), 1988; https://doi.org/10.3390/molecules24101988 (registering DOI)
Received: 23 April 2019 / Revised: 20 May 2019 / Accepted: 22 May 2019 / Published: 23 May 2019
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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 [...] Read more.
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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Open AccessArticle
Relationship Between G-Quadruplex Sequence Composition in Viruses and Their Hosts
Molecules 2019, 24(10), 1942; https://doi.org/10.3390/molecules24101942
Received: 2 May 2019 / Revised: 16 May 2019 / Accepted: 16 May 2019 / Published: 20 May 2019
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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+N1–7G3+ [...] Read more.
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+N1–7G3+N1–7G3+N1–7G3+ are widely found in eukaryotic and prokaryotic genomes, but the base composition of the N1-7 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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Open AccessArticle
A Novel G-Quadruplex Binding Protein in Yeast—Slx9
Molecules 2019, 24(9), 1774; https://doi.org/10.3390/molecules24091774
Received: 26 March 2019 / Revised: 2 May 2019 / Accepted: 3 May 2019 / Published: 7 May 2019
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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 [...] Read more.
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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Open AccessArticle
The Presence and Localization of G-Quadruplex Forming Sequences in the Domain of Bacteria
Molecules 2019, 24(9), 1711; https://doi.org/10.3390/molecules24091711
Received: 16 April 2019 / Revised: 30 April 2019 / Accepted: 1 May 2019 / Published: 2 May 2019
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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 [...] Read more.
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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Open AccessArticle
Conformational Dynamics of the RNA G-Quadruplex and its Effect on Translation Efficiency
Molecules 2019, 24(8), 1613; https://doi.org/10.3390/molecules24081613
Received: 12 April 2019 / Revised: 22 April 2019 / Accepted: 22 April 2019 / Published: 24 April 2019
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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, [...] Read more.
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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Open AccessArticle
Towards Understanding of Polymorphism of the G-rich Region of Human Papillomavirus Type 52
Molecules 2019, 24(7), 1294; https://doi.org/10.3390/molecules24071294
Received: 16 March 2019 / Revised: 29 March 2019 / Accepted: 31 March 2019 / Published: 2 April 2019
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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. [...] Read more.
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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Graphical abstract

Open AccessArticle
Intensive Distribution of G2-Quaduplexes in the Pseudorabies Virus Genome and Their Sensitivity to Cations and G-Quadruplex Ligands
Molecules 2019, 24(4), 774; https://doi.org/10.3390/molecules24040774
Received: 17 January 2019 / Revised: 13 February 2019 / Accepted: 15 February 2019 / Published: 21 February 2019
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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 [...] Read more.
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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Open AccessCommunication
In Cellulo Protein-mRNA Interaction Assay to Determine the Action of G-Quadruplex-Binding Molecules
Molecules 2018, 23(12), 3124; https://doi.org/10.3390/molecules23123124
Received: 8 November 2018 / Revised: 25 November 2018 / Accepted: 26 November 2018 / Published: 29 November 2018
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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 [...] Read more.
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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Open AccessReview
Parasitic Protozoa: Unusual Roles for G-Quadruplexes in Early-Diverging Eukaryotes
Molecules 2019, 24(7), 1339; https://doi.org/10.3390/molecules24071339
Received: 19 March 2019 / Revised: 2 April 2019 / Accepted: 3 April 2019 / Published: 5 April 2019
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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 [...] Read more.
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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