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Recent Advances of G-Quadruplexes In Vivo and In Vitro
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Recent Advances of G-Quadruplexes In Vivo and In Vitro

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

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 30305

Special Issue Editor

Dr. Ta-Chau Chang

E-Mail Website
Guest Editor
Institute of Atomic and Molecular Sciences&Genomics Research Center, Academia Sinica, Taipei 10617, Taiwan
Interests: spectroscopy and microscopy; small molecules in cancer research; G-quadruplex structures

Special Issue Information

Dear Colleagues,

G-quadruplex (G4) structures formed by the stacking of G-quartets with the Hoogsteen hydrogen bonding of four guanines under physiological conditions have recently gained much attention as possible targets for human cancer. Accumulating evidence on the biological functions of G4 structures in regulating multiple cellular processes support the existence of G4 structures in vivo. Recently, imaging-based studies on G4 antibodies and G4 ligands for visualizing the presence of G4s in cells showed more G4 formations in cancer cells than in normal cells. These findings lay the foundation for further studies about the details of G4 formation, and give deeper insight into G4 functions in vivo for a better understanding of the G4 structural biology at a molecular level. Another challenge in G4 research is structural determination. Given that the structural properties of G4s are critical for designing the theranostic G4 ligands for human cancer, many questions on structural variation as a result of sequence deviation are yet to be addressed. For example, different loop and flanking nucleotides in G-rich sequences may cause dramatic differences in G4 structures, even in vitro. In addition, the structural diversity and polymorphism of some G-rich sequences could pose more challenges for the structural analysis. More studies of the thermal stability and kinetic competition, as well as the folding and unfolding pathways of G4s may provide more comprehensive elucidation on such questions and challenges. The translation of G4 knowledge from in vitro to in vivo is currently a cutting-edge research in G4s. This Special Issue covers all aspects of the recent advances of G4 research, including sequence variation for G4 formations, G4 structures, G4 functions, G4 biology, G4 ligands, G4 specific antibodies, and, particularly, the development of methods and techniques for G4 research.

Dr. Ta-Chau Chang
Guest Editor

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Keywords

  • Sequence variation and G4 structure
  • Structural diversity and polymorphism
  • Folding dynamics of G4s
  • G4 biological functions
  • G4 ligands and G4 antibodies
  • Methods for structure determination
  • Techniques for monitoring G4 structures in cells

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Published Papers (8 papers)

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Research

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13 pages, 1741 KiB  
Article
Antisense Oligonucleotides Used to Identify Telomeric G-Quadruplexes in Metaphase Chromosomes and Fixed Cells by Fluorescence Lifetime Imaging Microscopy of o-BMVC Foci
by Ting-Yuan Tseng, Shin-Ya Liu, Chiung-Lin Wang and Ta-Chau Chang
Molecules 2020, 25(18), 4083; https://doi.org/10.3390/molecules25184083 - 7 Sep 2020
Cited by 7 | Viewed by 2820
Abstract
Identification of the existence of G-quadruplex (G4) structure, from a specific G-rich sequence in cells, is critical to the studies of structural biology and drug development. Accumulating evidence supports the existence of G4 structure in vivo. Particularly, time-gated fluorescence lifetime imaging microscopy (FLIM) [...] Read more.
Identification of the existence of G-quadruplex (G4) structure, from a specific G-rich sequence in cells, is critical to the studies of structural biology and drug development. Accumulating evidence supports the existence of G4 structure in vivo. Particularly, time-gated fluorescence lifetime imaging microscopy (FLIM) of a G4 fluorescent probe, 3,6-bis(1-methyl-2-vinylpyridinium) carbazole diiodide (o-BMVC), was used to quantitatively measure the number of G4 foci, not only in different cell lines, but also in tissue biopsy. Here, circular dichroism spectra and polyacrylamide gel electrophoresis assays show that the use of antisense oligonucleotides unfolds their G4 structures in different percentages. Using antisense oligonucleotides, quantitative measurement of the number of o-BMVC foci in time-gated FLIM images provides a method for identifying which G4 motifs form G4 structures in fixed cells. Here, the decrease of the o-BMVC foci number, upon the pretreatment of antisense sequences, (CCCTAA)3CCCTA, in fixed cells and at the end of metaphase chromosomes, allows us to identify the formation of telomeric G4 structures from TTAGGG repeats in fixed cells. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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12 pages, 1492 KiB  
Article
Custom G4 Microarrays Reveal Selective G-Quadruplex Recognition of Small Molecule BMVC: A Large-Scale Assessment of Ligand Binding Selectivity
by Guanhui Wu, Desiree Tillo, Sreejana Ray, Ta-Chau Chang, John S. Schneekloth, Jr., Charles Vinson and Danzhou Yang
Molecules 2020, 25(15), 3465; https://doi.org/10.3390/molecules25153465 - 30 Jul 2020
Cited by 16 | Viewed by 4022
Abstract
G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule [...] Read more.
G-quadruplexes (G4) are considered new drug targets for human diseases such as cancer. More than 10,000 G4s have been discovered in human chromatin, posing challenges for assessing the selectivity of a G4-interactive ligand. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent small molecule for G4 detection in vivo. Our previous structural study shows that BMVC binds to the MYC promoter G4 (MycG4) with high specificity. Here, we utilize high-throughput, large-scale custom DNA G4 microarrays to analyze the G4-binding selectivity of BMVC. BMVC preferentially binds to the parallel MycG4 and selectively recognizes flanking sequences of parallel G4s, especially the 3′-flanking thymine. Importantly, the microarray results are confirmed by orthogonal NMR and fluorescence binding analyses. Our study demonstrates the potential of custom G4 microarrays as a platform to broadly and unbiasedly assess the binding selectivity of G4-interactive ligands, and to help understand the properties that govern molecular recognition. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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18 pages, 4868 KiB  
Article
Effects of Length and Loop Composition on Structural Diversity and Similarity of (G3TG3NmG3TG3) G-Quadruplexes
by Jie Li, I-Te Chu, Ting-An Yeh, De-Yu Chen, Chiung-Lin Wang and Ta-Chau Chang
Molecules 2020, 25(8), 1779; https://doi.org/10.3390/molecules25081779 - 13 Apr 2020
Cited by 8 | Viewed by 2571
Abstract
A G-rich sequence containing three loops to connect four G-tracts with each ≥2 guanines can possibly form G-quadruplex structures. Given that all G-quadruplex structures comprise the stacking of G-quartets, the loop sequence plays a major role on their folding topology and thermal stability. [...] Read more.
A G-rich sequence containing three loops to connect four G-tracts with each ≥2 guanines can possibly form G-quadruplex structures. Given that all G-quadruplex structures comprise the stacking of G-quartets, the loop sequence plays a major role on their folding topology and thermal stability. Here circular dichroism, NMR, and PAGE are used to study the effect of loop length and base composition in the middle loop, and a single base difference in loop 1 and 3 on G-quadruplex formation of (G3HG3NmG3HG3) sequences with and without flanking nucleotides, where H is T, A, or C and N is T, A, C, or G. In addition, melting curve for G-quadruplex unfolding was used to provide relatively thermal stability of G-quadruplex structure after the addition of K+ overnight. We further studied the effects of K+ concentration on their stability and found structural changes in several sequences. Such (G3HG3NmG3HG3) configuration can be found in a number of native DNA sequences. The study of structural diversity and similarity from these sequences may allow us to establish the correlation between model sequences and native sequences. Moreover, several sequences upon interaction with a G-quadruplex ligand, BMVC, show similar spectral change, implying that structural similarity is crucial for drug development. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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11 pages, 2812 KiB  
Article
New Modified Deoxythymine with Dibranched Tetraethylene Glycol Stabilizes G-Quadruplex Structures
by Hisae Tateishi-Karimata, Tatsuya Ohyama, Takahiro Muraoka, Shigenori Tanaka, Kazushi Kinbara and Naoki Sugimoto
Molecules 2020, 25(3), 705; https://doi.org/10.3390/molecules25030705 - 6 Feb 2020
Cited by 5 | Viewed by 2870
Abstract
Methods for stabilizing G-quadruplex formation is a promising therapeutic approach for cancer treatment and other biomedical applications because stable G-quadruplexes efficiently inhibit biological reactions. Oligo and polyethylene glycols are promising biocompatible compounds, and we have shown that linear oligoethylene glycols can stabilize G-quadruplexes. [...] Read more.
Methods for stabilizing G-quadruplex formation is a promising therapeutic approach for cancer treatment and other biomedical applications because stable G-quadruplexes efficiently inhibit biological reactions. Oligo and polyethylene glycols are promising biocompatible compounds, and we have shown that linear oligoethylene glycols can stabilize G-quadruplexes. Here, we developed a new modified deoxythymine with dibranched or tribranched tetraethylene glycol (TEG) and incorporated these TEG-modified deoxythymines into a loop region that forms an antiparallel G-quadruplex. We analyzed the stability of the modified G-quadruplexes, and the results showed that the tribranched TEG destabilized G-quadruplexes through entropic contributions, likely through steric hindrance. Interestingly, the dibranched TEG modification increased G-quadruplex stability relative to the unmodified DNA structures due to favorable enthalpic contributions. Molecular dynamics calculations suggested that dibranched TEG interacts with the G-quadruplex through hydrogen bonding and CH-π interactions. Moreover, these branched TEG-modified deoxythymine protected the DNA oligonucleotides from degradation by various nucleases in human serum. By taking advantage of the unique interactions between DNA and branched TEG, advanced DNA materials can be developed that affect the regulation of DNA structure. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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10 pages, 1656 KiB  
Article
The Interaction of Cyclic Naphthalene Diimide with G-Quadruplex under Molecular Crowding Condition
by Tingting Zou, Shinobu Sato, Rui Yasukawa, Ryusuke Takeuchi, Shunsuke Ozaki, Satoshi Fujii and Shigeori Takenaka
Molecules 2020, 25(3), 668; https://doi.org/10.3390/molecules25030668 - 4 Feb 2020
Cited by 15 | Viewed by 3327
Abstract
G-quadruplex specific targeting molecules, also termed as G4 ligands, are attracting increasing attention for their ability to recognize and stabilize G-quadruplex and high potentiality for biological regulation. However, G4 ligands recognizing G-quadruplex were generally investigated within a dilute condition, which might be interfered [...] Read more.
G-quadruplex specific targeting molecules, also termed as G4 ligands, are attracting increasing attention for their ability to recognize and stabilize G-quadruplex and high potentiality for biological regulation. However, G4 ligands recognizing G-quadruplex were generally investigated within a dilute condition, which might be interfered with under a cellular crowding environment. Here, we designed and synthesized several new cyclic naphthalene diimide (cNDI) derivatives, and investigated their interaction with G-quadruplex under molecular crowding condition (40% v/v polyethylene glycol (PEG)200) to mimic the cellular condition. The results indicated that, under molecular crowding conditions, cNDI derivatives were still able to recognize and stabilize G-quadruplex structures based on circular dichroism measurement. The binding affinities were slightly decreased but still comparatively high upon determination by isothermal titration calorimetry and UV-vis absorbance spectroscopy. More interestingly, cNDI derivatives were observed with preference to induce a telomere sequence to form a hybrid G-quadruplex under cation-deficient molecular crowding conditions. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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14 pages, 2429 KiB  
Article
Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD
by Tim Božič, Matja Zalar, Boris Rogelj, Janez Plavec and Primož Šket
Molecules 2020, 25(3), 525; https://doi.org/10.3390/molecules25030525 - 25 Jan 2020
Cited by 11 | Viewed by 3815
Abstract
The hexanucleotide expansion GGGGCC located in C9orf72 gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G4C2 repeats involved in ALS [...] Read more.
The hexanucleotide expansion GGGGCC located in C9orf72 gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G4C2 repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could have a key role in pathogenesis of ALS and FTLD. Utilizing NMR spectroscopy and complementary methods, we examined structures adopted by both guanine-rich sense and cytosine-rich antisense RNA oligonucleotides with four hexanucleotide repeats. While both oligonucleotides tend to form dimers and hairpins, the equilibrium of these structures differs with antisense oligonucleotide being more sensitive to changes in pH and sense oligonucleotide to temperature. In the presence of K+ ions, guanine-rich sense RNA oligonucleotide also adopts secondary structures called G-quadruplexes. Here, we also observed, for the first time, that antisense RNA oligonucleotide forms i-motifs under specific conditions. Moreover, simultaneous presence of sense and antisense RNA oligonucleotides promotes formation of heterodimer. Studied structural diversity of sense and antisense RNA transcripts not only further depicts the complex nature of neurodegenerative diseases but also reveals potential targets for drug design in treatment of ALS and FTLD. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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18 pages, 1946 KiB  
Article
Chasing Particularities of Guanine- and Cytosine-Rich DNA Strands
by Marko Trajkovski and Janez Plavec
Molecules 2020, 25(3), 434; https://doi.org/10.3390/molecules25030434 - 21 Jan 2020
Cited by 6 | Viewed by 3085
Abstract
By substitution of natural nucleotides by their abasic analogs (i.e., 1′,2′-dideoxyribose phosphate residue) at critically chosen positions within 27-bp DNA constructs originating from the first intron of N-myc gene, we hindered hybridization within the guanine- and cytosine-rich central region and followed formation of [...] Read more.
By substitution of natural nucleotides by their abasic analogs (i.e., 1′,2′-dideoxyribose phosphate residue) at critically chosen positions within 27-bp DNA constructs originating from the first intron of N-myc gene, we hindered hybridization within the guanine- and cytosine-rich central region and followed formation of non-canonical structures. The impeded hybridization between the complementary strands leads to time-dependent structural transformations of guanine-rich strand that are herein characterized with the use of solution-state NMR, CD spectroscopy, and native polyacrylamide gel electrophoresis. Moreover, the DNA structural changes involve transformation of intra- into inter-molecular G-quadruplex structures that are thermodynamically favored. Intriguingly, the transition occurs in the presence of complementary cytosine-rich strands highlighting the inability of Watson–Crick base-pairing to preclude the transformation between G-quadruplex structures that occurs via intertwining mechanism and corroborates a role of G-quadruplex structures in DNA recombination processes. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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Review

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22 pages, 1568 KiB  
Review
G-Quadruplexes at Telomeres: Friend or Foe?
by Tracy M. Bryan
Molecules 2020, 25(16), 3686; https://doi.org/10.3390/molecules25163686 - 13 Aug 2020
Cited by 102 | Viewed by 7073
Abstract
Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, [...] Read more.
Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures. Full article
(This article belongs to the Special Issue Recent Advances of G-Quadruplexes In Vivo and In Vitro)
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