ijms-logo

Journal Browser

Journal Browser

The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (2 January 2023) | Viewed by 13853

Special Issue Editors

Special Issue Information

Dear Colleagues,

G-quadruplex structures are secondary conformations of nucleic acids, whose constitutive unit is the G-tetrad or G-quartet. This building block consists of a square planar arrangement of four guanosines, in which each base is associated to the adjacent ones through four hydrogen bonds. The stacking of two or more G-tetrad units can form larger and more stable structures. The occurrence of monovalent cations, between two adjacent G-tetrads or also in the center of a G-tetrad, further contributes to the structural stability of the G-quadruplex complexes. The biological significance of these DNA or RNA structures is witnessed by their occurrence or potential formation in several regions of the human genome, such as telomeres, genes promoters, and transcription start sites. Furthermore, they can be involved in the regulation of gene expression and telomere maintenance. However, the importance of the G-quadruplex structures is not confined to genetics and molecular biological research. In fact, thanks to their remarkable stability and outstanding variability, these structures constitute the scaffolds of several DNA or RNA aptamers, with important applications in pharmaceutics, analytics, and diagnostics. Furthermore, suitable G-quadruplexes are also endowed with catalytic properties. Moreover, considering their self-assembly properties, G-quadruplexes are often exploited in building nanostructures and in developing nanodevices.

This Special Issue will concern a selection of original research, review articles, and commentaries focused on diverse topics, with particular attention on the relationship between the structural features of the G-quadruplexes and their functional role.

Dr. Aldo Galeone
Dr. Veronica Esposito
Dr. Antonella Virgilio
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • G-quadruplex thermodynamics
  • G-quadruplex CD and fluorescence spectroscopy
  • G-quadruplex synthesis
  • G-quadruplex properties
  • G-quadruplex structure
  • G-quadruplex dynamics
  • G-quadruplex folding
  • G-quadruplex biological functions
  • G-quadruplex aptamers
  • G-quadruplex as a therapeutic target
  • catalytic G-quadruplexes

Published Papers (8 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

16 pages, 4598 KiB  
Article
Stability of Human Telomeric G-Quadruplexes Complexed with Photosensitive Ligands and Irradiated with Visible Light
by Valeria Libera, Francesca Ripanti, Caterina Petrillo, Francesco Sacchetti, Javier Ramos-Soriano, Maria Carmen Galan, Giorgio Schirò, Alessandro Paciaroni and Lucia Comez
Int. J. Mol. Sci. 2023, 24(10), 9090; https://doi.org/10.3390/ijms24109090 - 22 May 2023
Cited by 1 | Viewed by 1487
Abstract
Guanine-rich DNA sequences can fold into non-canonical nucleic acid structures called G-quadruplexes (G4s). These nanostructures have strong implications in many fields, from medical science to bottom-up nanotechnologies. As a result, ligands interacting with G4s have attracted great attention as candidates in medical therapies, [...] Read more.
Guanine-rich DNA sequences can fold into non-canonical nucleic acid structures called G-quadruplexes (G4s). These nanostructures have strong implications in many fields, from medical science to bottom-up nanotechnologies. As a result, ligands interacting with G4s have attracted great attention as candidates in medical therapies, molecular probe applications, and biosensing. In recent years, the use of G4-ligand complexes as photopharmacological targets has shown significant promise for developing novel therapeutic strategies and nanodevices. Here, we studied the possibility of manipulating the secondary structure of a human telomeric G4 sequence through the interaction with two photosensitive ligands, DTE and TMPyP4, whose response to visible light is different. The effect of these two ligands on G4 thermal unfolding was also considered, revealing the occurrence of peculiar multi-step melting pathways and the different attitudes of the two molecules on the quadruplex stabilization. Full article
Show Figures

Figure 1

23 pages, 9178 KiB  
Article
Novel Chiral Ru(II) Complexes as Potential c-myc G-quadruplex DNA Stabilizers Inducing DNA Damage to Suppress Triple-Negative Breast Cancer Progression
by Chanling Yuan, Zhixiang Wang, Zongtao Wang, Wentao Liu, Guohu Li, Jinlan Meng, Ruzhen Wu, Qiong Wu, Jiacheng Wang and Wenjie Mei
Int. J. Mol. Sci. 2023, 24(1), 203; https://doi.org/10.3390/ijms24010203 - 22 Dec 2022
Cited by 3 | Viewed by 1528
Abstract
Currently, effective drugs for triple-negative breast cancer (TNBC) are lacking in clinics. c-myc is one of the core members during TNBC tumorigenesis, and G-rich sequences in the promoter region can form a G-quadruplex conformation, indicating that the c-myc inhibitor is a possible strategy [...] Read more.
Currently, effective drugs for triple-negative breast cancer (TNBC) are lacking in clinics. c-myc is one of the core members during TNBC tumorigenesis, and G-rich sequences in the promoter region can form a G-quadruplex conformation, indicating that the c-myc inhibitor is a possible strategy to fight cancer. Herein, a series of chiral ruthenium(II) complexes ([Ru(bpy)2(DPPZ-R)](ClO4)2, Λ/Δ−1: R = -H, Λ/Δ−2: R = -Br, Λ/Δ−3: R = -C≡C(C6H4)NH2) were researched based on their interaction with c-myc G-quadruplex DNA. Λ3 and Δ3 show high affinity and stability to decrease their replication. Additional studies showed that Λ3 and Δ3 exhibit higher inhibition against different tumor cells than other molecules. Δ3 decreases the viability of MDA-MB-231 cells with an IC50 of 25.51 μM, which is comparable with that of cisplatin, with an IC50 of 25.9 μM. Moreover, Δ3 exhibits acceptable cytotoxic activity against MDA-MB-231 cells in a zebrafish xenograft breast cancer model. Further studies suggested that Δ3 decreases the viability of MDA-MB-231 cells predominantly through DNA-damage-mediated apoptosis, which may be because Δ3 can induce DNA damage. In summary, the results indicate that Ru(II) complexes containing alkinyl groups can be developed as c-myc G-quadruplex DNA binders to block TNBC progression. Full article
Show Figures

Graphical abstract

16 pages, 5044 KiB  
Article
Investigation of the Interaction between Aloe vera Anthraquinone Metabolites and c-Myc and C-Kit G-Quadruplex DNA Structures
by Sabrina Dallavalle, Roberto Artali, Salvatore Princiotto, Loana Musso, Gigliola Borgonovo and Stefania Mazzini
Int. J. Mol. Sci. 2022, 23(24), 16018; https://doi.org/10.3390/ijms232416018 - 16 Dec 2022
Cited by 1 | Viewed by 1260
Abstract
G-quadruplexes are nucleotide sequences present in the promoter region of numerous oncogenes, having a key role in the suppression of gene transcription. Recently, the binding of anthraquinones from Aloe vera to G-quadruplex structures has been studied through various physico-chemical techniques. Intrigued by the [...] Read more.
G-quadruplexes are nucleotide sequences present in the promoter region of numerous oncogenes, having a key role in the suppression of gene transcription. Recently, the binding of anthraquinones from Aloe vera to G-quadruplex structures has been studied through various physico-chemical techniques. Intrigued by the reported results, we investigated the affinity of aloe emodin, aloe emodin-8-glucoside, and aloin to selected G-quadruplex nucleotide sequences by NMR spectroscopy. The structural determinants for the formation of the ligand/nucleotide complexes were elucidated and a model of the interactions between the tested compounds and C-Kit and c-Myc G-quadruplex DNA structures was built by integrated NMR and molecular modeling studies. Overall, the obtained results confirmed and implemented the previously reported findings, pointing out the complementarity of the different approaches and their contribution to a more detailed overview of the ligand/nucleotide complex formation. Furthermore, the proposed models of interaction could pave the way to the design of new nature-derived compounds endowed with increased G-quadruplex stabilizing activity. Full article
Show Figures

Figure 1

12 pages, 1586 KiB  
Article
Properties and Potential Antiproliferative Activity of Thrombin-Binding Aptamer (TBA) Derivatives with One or Two Additional G-Tetrads
by Daniela Benigno, Antonella Virgilio, Ivana Bello, Sara La Manna, Valentina Vellecco, Mariarosaria Bucci, Daniela Marasco, Elisabetta Panza, Veronica Esposito and Aldo Galeone
Int. J. Mol. Sci. 2022, 23(23), 14921; https://doi.org/10.3390/ijms232314921 - 29 Nov 2022
Cited by 3 | Viewed by 1385
Abstract
In this paper, we study the biological properties of two TBA analogs containing one and two extra G-tetrads, namely TBAG3 and TBAG4, respectively, and two further derivatives in which one of the small loops at the bottom (TBAG41S) or the large loop at [...] Read more.
In this paper, we study the biological properties of two TBA analogs containing one and two extra G-tetrads, namely TBAG3 and TBAG4, respectively, and two further derivatives in which one of the small loops at the bottom (TBAG41S) or the large loop at the top (TBAG4GS) of the TBAG4 structure has been completely modified by replacing all loop residues with abasic site mimics. The therapeutical development of the TBA was hindered by its low thermodynamic and nuclease stability, while its potential as an anticancer/antiproliferative molecule is also affected by the anticoagulant activity, being a side effect in this case. In order to obtain suitable TBA analogs and to explore the involvement of specific aptamer regions in biological activity, the antiproliferative capability against DU 145 and MDAMB 231 cancer cell lines (MTT), the anticoagulant properties (PT), the biological degradability (nuclease stability assay) and nucleolin (NCL) binding ability (SPR) of the above described TBA derivatives have been tested. Interestingly, none of the TBA analogs exhibits an anticoagulant activity, while all of them show antiproliferative properties to the same extent. Furthermore, TBAG4 displays extraordinary nuclease stability and promising antiproliferative properties against breast cancer cells binding NCL efficiently. These results expand the range of G4-structures targeting NCL and the possibility of developing novel anticancer and antiviral drugs. Full article
Show Figures

Figure 1

12 pages, 1786 KiB  
Article
Novel Planar Pt(II) Cyclometallated Cytotoxic Complexes with G-Quadruplex Stabilisation and Luminescent Properties
by Brondwyn S. McGhie, Jennette Sakoff, Jayne Gilbert, Christopher P. Gordon and Janice R. Aldrich-Wright
Int. J. Mol. Sci. 2022, 23(18), 10469; https://doi.org/10.3390/ijms231810469 - 9 Sep 2022
Cited by 7 | Viewed by 1320
Abstract
Herein is described the development of a series of novel quadruplex DNA (QDNA)-stabilising cyclometallated square–planar metal complexes (CMCs). Melting experiments using quadruplex DNA (QDNA) demonstrated that interactions with the complexes increased the melting temperature by up to 19 °C. This QDNA stabilisation was [...] Read more.
Herein is described the development of a series of novel quadruplex DNA (QDNA)-stabilising cyclometallated square–planar metal complexes (CMCs). Melting experiments using quadruplex DNA (QDNA) demonstrated that interactions with the complexes increased the melting temperature by up to 19 °C. This QDNA stabilisation was determined in two of the major G-quadruplex structures formed in the human c-MYC promoter gene (c-MYC) and a human telomeric repeat sequence (H-Telo). The CMCs were found to stabilise H-telo more strongly than c-MYC, and the CMCs with the highest cytotoxic effect had a low–moderate correlation between H-telo binding capacity and cytotoxicity (R2 values up to 10 times those of c-MYC). The melting experiments further revealed that the stabilisation effect was altered depending on whether the CMC was introduced before or after the formation of QDNA. All CMCs’ GI50 values were comparable or better than cisplatin in human cancer cell lines HT29, U87, MCF-7, H460, A431, Du145, BE2-C, SJ-G2, MIA, and ADDP. Complexes 6, 7, and 9 were significantly more cytotoxic than cisplatin in all cell lines tested and had good to moderate selectivity indices, 1.7–4.5 in MCF10A/MCF-7. The emission quantum yields were determined to be relatively high (up to 0.064), and emission occurred outside cellular autofluorescence, meaning CMC fluorescence is ideal for in vitro analyses. Full article
Show Figures

Graphical abstract

18 pages, 2189 KiB  
Article
Impact of G-Quadruplex Structures on Methylation of Model Substrates by DNA Methyltransferase Dnmt3a
by Andrei G. Loiko, Alexander V. Sergeev, Adelya I. Genatullina, Mayya V. Monakhova, Elena A. Kubareva, Nina G. Dolinnaya and Elizaveta S. Gromova
Int. J. Mol. Sci. 2022, 23(18), 10226; https://doi.org/10.3390/ijms231810226 - 6 Sep 2022
Cited by 2 | Viewed by 1716
Abstract
In mammals, de novo methylation of cytosines in DNA CpG sites is performed by DNA methyltransferase Dnmt3a. Changes in the methylation status of CpG islands are critical for gene regulation and for the progression of some cancers. Recently, the potential involvement of DNA [...] Read more.
In mammals, de novo methylation of cytosines in DNA CpG sites is performed by DNA methyltransferase Dnmt3a. Changes in the methylation status of CpG islands are critical for gene regulation and for the progression of some cancers. Recently, the potential involvement of DNA G-quadruplexes (G4s) in methylation control has been found. Here, we provide evidence for a link between G4 formation and the function of murine DNA methyltransferase Dnmt3a and its individual domains. As DNA models, we used (i) an isolated G4 formed by oligonucleotide capable of folding into parallel quadruplex and (ii) the same G4 inserted into a double-stranded DNA bearing several CpG sites. Using electrophoretic mobility shift and fluorescence polarization assays, we showed that the Dnmt3a catalytic domain (Dnmt3a-CD), in contrast to regulatory PWWP domain, effectively binds the G4 structure formed in both DNA models. The G4-forming oligonucleotide displaced the DNA substrate from its complex with Dnmt3a-CD, resulting in a dramatic suppression of the enzyme activity. In addition, a direct impact of G4 inserted into the DNA duplex on the methylation of a specific CpG site was revealed. Possible mechanisms of G4-mediated epigenetic regulation may include Dnmt3a sequestration at G4 and/or disruption of Dnmt3a oligomerization on the DNA surface. Full article
Show Figures

Figure 1

20 pages, 2394 KiB  
Article
Modulation of Aptamer–Ligand-Binding by Complementary Oligonucleotides: A G-Quadruplex Anti-Ochratoxin A Aptamer Case Study
by Alexey V. Samokhvalov, Irina V. Safenkova, Sergei A. Eremin, Artem N. Bonchuk, Oksana G. Maksimenko, Nikolai N. Sluchanko, Anatoly V. Zherdev and Boris B. Dzantiev
Int. J. Mol. Sci. 2022, 23(9), 4876; https://doi.org/10.3390/ijms23094876 - 28 Apr 2022
Cited by 4 | Viewed by 2161
Abstract
Short oligonucleotides are widely used for the construction of aptamer-based sensors and logical bioelements to modulate aptamer–ligand binding. However, relationships between the parameters (length, location of the complementary region) of oligonucleotides and their influence on aptamer–ligand interactions remain unclear. Here, we addressed this [...] Read more.
Short oligonucleotides are widely used for the construction of aptamer-based sensors and logical bioelements to modulate aptamer–ligand binding. However, relationships between the parameters (length, location of the complementary region) of oligonucleotides and their influence on aptamer–ligand interactions remain unclear. Here, we addressed this task by comparing the effects of short complementary oligonucleotides (ssDNAs) on the structure and ligand-binding ability of an aptamer and identifying ssDNAs’ features that determine these effects. Within this, the interactions between the OTA-specific G-quadruplex aptamer 1.12.2 (5′-GATCGGGTGTGGGTGGCGTAAAGGGA GCATCGGACA-3′) and 21 single-stranded DNA (ssDNA) oligonucleotides complementary to different regions of the aptamer were studied. Two sets of aptamer–ssDNA dissociation constants were obtained in the absence and in the presence of OTA by isothermal calorimetry and fluorescence anisotropy, respectively. In both sets, the binding constants depend on the number of hydrogen bonds formed in the aptamer–ssDNA complex. The ssDNAs’ having more than 23 hydrogen bonds with the aptamer have a lower aptamer dissociation constant than for aptamer–OTA interactions. The ssDNAs’ having less than 18 hydrogen bonds did not affect the aptamer–OTA affinity. The location of ssDNA’s complementary site in the aptamer affeced the kinetics of the interaction and retention of OTA-binding in aptamer–ssDNA complexes. The location of the ssDNA site in the aptamer G-quadruplex led to its unfolding. In the presence of OTA, the unfolding process was longer and takes from 20 to 70 min. The refolding in the presence of OTA was possible and depends on the length and location of the ssDNA’s complementary site. The location of the ssDNA site in the tail region led to its rapid displacement and wasn’t affecting the G-qaudruplex’s integrity. It makes the tail region more perspective for the development of ssDNA-based tools using this aptamer. Full article
Show Figures

Figure 1

Review

Jump to: Research

16 pages, 725 KiB  
Review
G-Quadruplexes in Repeat Expansion Disorders
by Ye Teng, Ming Zhu and Zhidong Qiu
Int. J. Mol. Sci. 2023, 24(3), 2375; https://doi.org/10.3390/ijms24032375 - 25 Jan 2023
Cited by 4 | Viewed by 2158
Abstract
The repeat expansions are the main genetic cause of various neurodegeneration diseases. More than ten kinds of repeat sequences with different lengths, locations, and structures have been confirmed in the past two decades. G-rich repeat sequences, such as CGG and GGGGCC, are reported [...] Read more.
The repeat expansions are the main genetic cause of various neurodegeneration diseases. More than ten kinds of repeat sequences with different lengths, locations, and structures have been confirmed in the past two decades. G-rich repeat sequences, such as CGG and GGGGCC, are reported to form functional G-quadruplexes, participating in many important bioprocesses. In this review, we conducted an overview concerning the contribution of G-quadruplex in repeat expansion disorders and summarized related mechanisms in current pathological studies, including the increasing genetic instabilities in replication and transcription, the toxic RNA foci formed in neurons, and the loss/gain function of proteins and peptides. Furthermore, novel strategies targeting G-quadruplex repeats were developed based on the understanding of disease mechanism. Small molecules and proteins binding to G-quadruplex in repeat expansions were investigated to protect neurons from dysfunction and delay the progression of neurodegeneration. In addition, the effects of environment on the stability of G-quadruplex were discussed, which might be critical factors in the pathological study of repeat expansion disorders. Full article
Show Figures

Figure 1

Back to TopTop