Journal articles: 'DNA, G-quadruplex, structure'

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Winnerdy, Fernaldo Richtia, Blaž Bakalar, Arijit Maity, J. Jeya Vandana, Yves Mechulam, Emmanuelle Schmitt, and Anh Tuân Phan. "NMR solution and X-ray crystal structures of a DNA molecule containing both right- and left-handed parallel-stranded G-quadruplexes." Nucleic Acids Research 47, no. 15 (June 19, 2019): 8272–81. http://dx.doi.org/10.1093/nar/gkz349.

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AbstractAnalogous to the B- and Z-DNA structures in double-helix DNA, there exist both right- and left-handed quadruple-helix (G-quadruplex) DNA. Numerous conformations of right-handed and a few left-handed G-quadruplexes were previously observed, yet they were always identified separately. Here, we present the NMR solution and X-ray crystal structures of a right- and left-handed hybrid G-quadruplex. The structure reveals a stacking interaction between two G-quadruplex blocks with different helical orientations and displays features of both right- and left-handed G-quadruplexes. An analysis of loop mutations suggests that single-nucleotide loops are preferred or even required for the left-handed G-quadruplex formation. The discovery of a right- and left-handed hybrid G-quadruplex further expands the polymorphism of G-quadruplexes and is potentially useful in designing a left-to-right junction in G-quadruplex engineering.

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Olejko, Lydia, Anushree Dutta, Kosar Shahsavar, and Ilko Bald. "Influence of Different Salts on the G-Quadruplex Structure Formed from the Reversed Human Telomeric DNA Sequence." International Journal of Molecular Sciences 23, no. 20 (October 13, 2022): 12206. http://dx.doi.org/10.3390/ijms232012206.

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G-rich telomeric DNA plays a major role in the stabilization of chromosomes and can fold into a plethora of different G-quadruplex structures in the presence of mono- and divalent cations. The reversed human telomeric DNA sequence (5′-(GGG ATT)4; RevHumTel) was previously shown to have interesting properties that can be exploited for chemical sensing and as a chemical switch in DNA nanotechnology. Here, we analyze the specific G-quadruplex structures formed by RevHumTel in the presence of K+, Na+, Mg2+ and Ca2+ cations using circular dichroism spectroscopy (CDS) and Förster resonance energy transfer (FRET) based on fluorescence lifetimes. CDS is able to reveal strand and loop orientations, whereas FRET gives information about the distances between the 5′-end and the 3′-end, and also, the number of G-quadruplex species formed. Based on this combined information we derived specific G-quadruplex structures formed from RevHumTel, i.e., a chair-type and a hybrid-type G-quadruplex structure formed in presence of K+, whereas Na+ induces the formation of up to three different G-quadruplexes (a basket-type, a propeller-type and a hybrid-type structure). In the presence of Mg2+ and Ca2+ two different parallel G-quadruplexes are formed (one of which is a propeller-type structure). This study will support the fundamental understanding of the G-quadruplex formation in different environments and a rational design of G-quadruplex-based applications in sensing and nanotechnology.

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Heddi, Brahim, Vee Vee Cheong, Herry Martadinata, and Anh Tuân Phan. "Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex." Proceedings of the National Academy of Sciences 112, no. 31 (July 20, 2015): 9608–13. http://dx.doi.org/10.1073/pnas.1422605112.

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Four-stranded nucleic acid structures called G-quadruplexes have been associated with important cellular processes, which should require G-quadruplex–protein interaction. However, the structural basis for specific G-quadruplex recognition by proteins has not been understood. The DEAH (Asp-Glu-Ala-His) box RNA helicase associated with AU-rich element (RHAU) (also named DHX36 or G4R1) specifically binds to and resolves parallel-stranded G-quadruplexes. Here we identified an 18-amino acid G-quadruplex-binding domain of RHAU and determined the structure of this peptide bound to a parallel DNA G-quadruplex. Our structure explains how RHAU specifically recognizes parallel G-quadruplexes. The peptide covers a terminal guanine base tetrad (G-tetrad), and clamps the G-quadruplex using three-anchor-point electrostatic interactions between three positively charged amino acids and negatively charged phosphate groups. This binding mode is strikingly similar to that of most ligands selected for specific G-quadruplex targeting. Binding to an exposed G-tetrad represents a simple and efficient way to specifically target G-quadruplex structures.

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Traczyk, Anna, Chong Wai Liew, David James Gill, and Daniela Rhodes. "Structural basis of G-quadruplex DNA recognition by the yeast telomeric protein Rap1." Nucleic Acids Research 48, no. 8 (March 18, 2020): 4562–71. http://dx.doi.org/10.1093/nar/gkaa171.

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Abstract G-quadruplexes are four-stranded nucleic acid structures involved in multiple cellular pathways including DNA replication and telomere maintenance. Such structures are formed by G-rich DNA sequences typified by telomeric DNA repeats. Whilst there is evidence for proteins that bind and regulate G-quadruplex formation, the molecular basis for this remains poorly understood. The budding yeast telomeric protein Rap1, originally identified as a transcriptional regulator functioning by recognizing double-stranded DNA binding sites, was one of the first proteins to be discovered to also bind and promote G-quadruplex formation in vitro. Here, we present the 2.4 Å resolution crystal structure of the Rap1 DNA-binding domain in complex with a G-quadruplex. Our structure not only provides a detailed insight into the structural basis for G-quadruplex recognition by a protein, but also gives a mechanistic understanding of how the same DNA-binding domain adapts to specifically recognize different DNA structures. The key observation is the DNA-recognition helix functions in a bimodal manner: In double-stranded DNA recognition one helix face makes electrostatic interactions with the major groove of DNA, whereas in G-quadruplex recognition a different helix face is used to make primarily hydrophobic interactions with the planar face of a G-tetrad.

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Parekh, Virali J., Brittany A. Niccum, Rachna Shah, Marisa A. Rivera, Mark J. Novak, Frederic Geinguenaud, Frank Wien, Véronique Arluison, and Richard R. Sinden. "Role of Hfq in Genome Evolution: Instability of G-Quadruplex Sequences in E. coli." Microorganisms 8, no. 1 (December 22, 2019): 28. http://dx.doi.org/10.3390/microorganisms8010028.

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Certain G-rich DNA repeats can form quadruplex in bacterial chromatin that can present blocks to DNA replication and, if not properly resolved, may lead to mutations. To understand the participation of quadruplex DNA in genomic instability in Escherichia coli (E. coli), mutation rates were measured for quadruplex-forming DNA repeats, including (G3T)4, (G3T)8, and a RET oncogene sequence, cloned as the template or nontemplate strand. We evidence that these alternative structures strongly influence mutagenesis rates. Precisely, our results suggest that G-quadruplexes form in E. coli cells, especially during transcription when the G-rich strand can be displaced by R-loop formation. Structure formation may then facilitate replication misalignment, presumably associated with replication fork blockage, promoting genomic instability. Furthermore, our results also evidence that the nucleoid-associated protein Hfq is involved in the genetic instability associated with these sequences. Hfq binds and stabilizes G-quadruplex structure in vitro and likely in cells. Collectively, our results thus implicate quadruplexes structures and Hfq nucleoid protein in the potential for genetic change that may drive evolution or alterations of bacterial gene expression.

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Tateishi-Karimata, Hisae, Tatsuya Ohyama, Takahiro Muraoka, Shigenori Tanaka, Kazushi Kinbara, and Naoki Sugimoto. "New Modified Deoxythymine with Dibranched Tetraethylene Glycol Stabilizes G-Quadruplex Structures." Molecules 25, no. 3 (February 6, 2020): 705. http://dx.doi.org/10.3390/molecules25030705.

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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.

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Lerner, Leticia Koch, and Julian E. Sale. "Replication of G Quadruplex DNA." Genes 10, no. 2 (January 29, 2019): 95. http://dx.doi.org/10.3390/genes10020095.

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A cursory look at any textbook image of DNA replication might suggest that the complex machine that is the replisome runs smoothly along the chromosomal DNA. However, many DNA sequences can adopt non-B form secondary structures and these have the potential to impede progression of the replisome. A picture is emerging in which the maintenance of processive DNA replication requires the action of a significant number of additional proteins beyond the core replisome to resolve secondary structures in the DNA template. By ensuring that DNA synthesis remains closely coupled to DNA unwinding by the replicative helicase, these factors prevent impediments to the replisome from causing genetic and epigenetic instability. This review considers the circumstances in which DNA forms secondary structures, the potential responses of the eukaryotic replisome to these impediments in the light of recent advances in our understanding of its structure and operation and the mechanisms cells deploy to remove secondary structure from the DNA. To illustrate the principles involved, we focus on one of the best understood DNA secondary structures, G quadruplexes (G4s), and on the helicases that promote their resolution.

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Sun, Zhi-Yin, Xiao-Na Wang, Sui-Qi Cheng, Xiao-Xuan Su, and Tian-Miao Ou. "Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction." Molecules 24, no. 3 (January 22, 2019): 396. http://dx.doi.org/10.3390/molecules24030396.

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G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.

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Wu, Guanhui, Luying Chen, Wenting Liu, and Danzhou Yang. "Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres." Molecules 24, no. 8 (April 22, 2019): 1578. http://dx.doi.org/10.3390/molecules24081578.

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G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.

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Hellman, Lance M., Tyler J. Spear, Colton J. Koontz, Manana Melikishvili, and Michael G. Fried. "Repair of O6-methylguanine adducts in human telomeric G-quadruplex DNA by O6-alkylguanine-DNA alkyltransferase." Nucleic Acids Research 42, no. 15 (July 30, 2014): 9781–91. http://dx.doi.org/10.1093/nar/gku659.

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Abstract O 6-alkylguanine-DNA alkyltransferase (AGT) is a single-cycle DNA repair enzyme that removes pro-mutagenic O6-alkylguanine adducts from DNA. Its functions with short single-stranded and duplex substrates have been characterized, but its ability to act on other DNA structures remains poorly understood. Here, we examine the functions of this enzyme on O6-methylguanine (6mG) adducts in the four-stranded structure of the human telomeric G-quadruplex. On a folded 22-nt G-quadruplex substrate, binding saturated at 2 AGT:DNA, significantly less than the ∼5 AGT:DNA found with linear single-stranded DNAs of similar length, and less than the value found with the telomere sequence under conditions that inhibit quadruplex formation (4 AGT:DNA). Despite these differences, AGT repaired 6mG adducts located within folded G-quadruplexes, at rates that were comparable to those found for a duplex DNA substrate under analogous conditions. Repair was kinetically biphasic with the amplitudes of rapid and slow phases dependent on the position of the adduct within the G-quadruplex: in general, adducts located in the top or bottom tetrads of a quadruplex stack exhibited more rapid-phase repair than did adducts located in the inner tetrad. This distinction may reflect differences in the conformational dynamics of 6mG residues in G-quadruplex DNAs.

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Ghosh, Meenakshi, and Mahavir Singh. "Structure specific recognition of telomeric repeats containing RNA by the RGG-box of hnRNPA1." Nucleic Acids Research 48, no. 8 (March 4, 2020): 4492–506. http://dx.doi.org/10.1093/nar/gkaa134.

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Abstract The telomere repeats containing RNA (TERRA) is transcribed from the C-rich strand of telomere DNA and comprises of UUAGGG nucleotides repeats in humans. The TERRA RNA repeats can exist in single stranded, RNA-DNA hybrid and G-quadruplex forms in the cell. Interaction of TERRA RNA with hnRNPA1 has been proposed to play critical roles in maintenance of telomere DNA. hnRNPA1 contains an N-terminal UP1 domain followed by an RGG-box containing C-terminal region. RGG-motifs are emerging as key protein motifs that recognize the higher order nucleic acid structures as well as are known to promote liquid-liquid phase separation of proteins. In this study, we have shown that the RGG-box of hnRNPA1 specifically recognizes the TERRA RNA G-quadruplexes that have loops in their topology, whereas it does not interact with the single-stranded RNA. Our results show that the N-terminal UP1 domain in the presence of the RGG-box destabilizes the loop containing TERRA RNA G-quadruplex efficiently compared to the RNA G-quadruplex that lacks loops, suggesting that unfolding of G-quadruplex structures by UP1 is structure dependent. Furthermore, we have compared the telomere DNA and TERRA RNA G-quadruplex binding by the RGG-box of hnRNPA1 and discussed its implications in telomere DNA maintenance.

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Chung, Wan Jun, Brahim Heddi, Emmanuelle Schmitt, Kah Wai Lim, Yves Mechulam, and Anh Tuân Phan. "Structure of a left-handed DNA G-quadruplex." Proceedings of the National Academy of Sciences 112, no. 9 (February 18, 2015): 2729–33. http://dx.doi.org/10.1073/pnas.1418718112.

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Aside from the well-known double helix, DNA can also adopt an alternative four-stranded structure known as G-quadruplex. Implications of such a structure in cellular processes, as well as its therapeutic and diagnostic applications, have been reported. The G-quadruplex structure is highly polymorphic, but so far, only right-handed helical forms have been observed. Here we present the NMR solution and X-ray crystal structures of a left-handed DNA G-quadruplex. The structure displays unprecedented features that can be exploited as unique recognition elements.

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Platella, Chiara, Rosa Gaglione, Ettore Napolitano, Angela Arciello, Valentina Pirota, Filippo Doria, Domenica Musumeci, and Daniela Montesarchio. "DNA Binding Mode Analysis of a Core-Extended Naphthalene Diimide as a Conformation-Sensitive Fluorescent Probe of G-Quadruplex Structures." International Journal of Molecular Sciences 22, no. 19 (September 30, 2021): 10624. http://dx.doi.org/10.3390/ijms221910624.

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G-quadruplex existence was proved in cells by using both antibodies and small molecule fluorescent probes. However, the G-quadruplex probes designed thus far are structure- but not conformation-specific. Recently, a core-extended naphthalene diimide (cex-NDI) was designed and found to provide fluorescent signals of markedly different intensities when bound to G-quadruplexes of different conformations or duplexes. Aiming at evaluating how the fluorescence behaviour of this compound is associated with specific binding modes to the different DNA targets, cex-NDI was here studied in its interaction with hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex models by biophysical techniques, molecular docking, and biological assays. cex-NDI showed different binding modes associated with different amounts of stacking interactions with the three DNA targets. The preferential binding sites were the groove, outer quartet, or intercalative site of the hybrid G-quadruplex, parallel G-quadruplex, and B-DNA duplex, respectively. Interestingly, our data show that the fluorescence intensity of DNA-bound cex-NDI correlates with the amount of stacking interactions formed by the ligand with each DNA target, thus providing the rationale behind the conformation-sensitive properties of cex-NDI and supporting its use as a fluorescent probe of G-quadruplex structures. Notably, biological assays proved that cex-NDI mainly localizes in the G-quadruplex-rich nuclei of cancer cells.

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Truong, Tuom TT, Trang PT Phan, Linh TT Le, Dung H. Nguyen, Hoang D. Nguyen, and Dung Thanh Dang. "Engineering yellow fluorescent protein probe for visualization of parallel DNA G-quadruplex." Science and Technology Development Journal 21, no. 3 (November 9, 2018): 84–89. http://dx.doi.org/10.32508/stdj.v21i3.461.

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Introduction: The formation of G-quadruplex plays a key role in many biological processes. Therefore, visualization of G-quadruplex is highly essential for design of G-quadruplex-targeted small molecules (drugs). Herein, we report on an engineered fluorescent protein probe which was able to distinguish G-quadruplex topologies. Methods: The fluorescent protein probe was generated by genetically incorporating yellow fluorescent protein (YFP) to RNA helicase associated with AU-rich element (RHAU) peptide motif. Results: This probe could selectively bind and visualize parallel G-quadruplex structure (T95-2T) at high affinity (Kd~130 nM). Visualization of the parallel G-quadruplex by RHAU-YFP could be easily observed in vitro by using normal Gel Doc or the naked eye. Conclusion: The YFP probe could be encoded in cells to provide a powerful tool for detection of parallel G-quadruplexes both in vitro and in vivo.

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Tassinari, Martina, Michela Zuffo, Matteo Nadai, Valentina Pirota, Adriana Carolina Sevilla Montalvo, Filippo Doria, Mauro Freccero, and Sara N. Richter. "Selective targeting of mutually exclusive DNA G-quadruplexes: HIV-1 LTR as paradigmatic model." Nucleic Acids Research 48, no. 9 (April 13, 2020): 4627–42. http://dx.doi.org/10.1093/nar/gkaa186.

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Abstract Targeting of G-quadruplexes, non-canonical conformations that form in G-rich regions of nucleic acids, has been proposed as a novel therapeutic strategy toward several diseases, including cancer and infections. The unavailability of highly selective molecules targeting a G-quadruplex of choice has hampered relevant applications. Herein, we describe a novel approach, based on naphthalene diimide (NDI)-peptide nucleic acid (PNA) conjugates, taking advantage of the cooperative interaction of the NDI with the G-quadruplex structure and hybridization of the PNA with the flanking region upstream or downstream the targeted G-quadruplex. By biophysical and biomolecular assays, we show that the NDI-PNA conjugates are able to specifically recognize the G-quadruplex of choice within the HIV-1 LTR region, consisting of overlapping and therefore mutually exclusive G-quadruplexes. Additionally, the conjugates can induce and stabilize the least populated G-quadruplex at the expenses of the more stable ones. The general and straightforward design and synthesis, which readily apply to any G4 target of choice, together with both the red-fluorescent emission and the possibility to introduce cellular localization signals, make the novel conjugates available to selectively control G-quadruplex folding over a wide range of applications.

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Geng, Yanyan, Changdong Liu, Qixu Cai, Zhipu Luo, Haitao Miao, Xiao Shi, Naining Xu, et al. "Crystal structure of parallel G-quadruplex formed by the two-repeat ALS- and FTD-related GGGGCC sequence." Nucleic Acids Research 49, no. 10 (May 28, 2021): 5881–90. http://dx.doi.org/10.1093/nar/gkab302.

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Abstract The hexanucleotide repeat expansion, GGGGCC (G4C2), within the first intron of the C9orf72 gene is known to be the most common genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The G4C2 repeat expansions, either DNA or RNA, are able to form G-quadruplexes which induce toxicity leading to ALS/FTD. Herein, we report a novel crystal structure of d(G4C2)2 that self-associates to form an eight-layer parallel tetrameric G-quadruplex. Two d(G4C2)2 associate together as a parallel dimeric G-quadruplex which folds into a tetramer via 5′-to-5′ arrangements. Each dimer consists of four G-tetrads connected by two CC propeller loops. Especially, the 3′-end cytosines protrude out and form C·C+•C·C+/ C·C•C·C+ quadruple base pair or C•C·C+ triple base pair stacking on the dimeric block. Our work sheds light on the G-quadruplexes adopted by d(G4C2) and yields the invaluable structural details for the development of small molecules to tackle neurodegenerative diseases, ALS and FTD.

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Puig Lombardi, Emilia, and Arturo Londoño-Vallejo. "A guide to computational methods for G-quadruplex prediction." Nucleic Acids Research 48, no. 1 (November 22, 2019): 1–15. http://dx.doi.org/10.1093/nar/gkz1097.

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Abstract Guanine-rich nucleic acids can fold into the non-B DNA or RNA structures called G-quadruplexes (G4). Recent methodological developments have allowed the characterization of specific G-quadruplex structures in vitro as well as in vivo, and at a much higher throughput, in silico, which has greatly expanded our understanding of G4-associated functions. Typically, the consensus motif G3+N1–7G3+N1–7G3+N1–7G3+ has been used to identify potential G-quadruplexes from primary sequence. Since, various algorithms have been developed to predict the potential formation of quadruplexes directly from DNA or RNA sequences and the number of studies reporting genome-wide G4 exploration across species has rapidly increased. More recently, new methodologies have also appeared, proposing other estimates which consider non-canonical sequences and/or structure propensity and stability. The present review aims at providing an updated overview of the current open-source G-quadruplex prediction algorithms and straightforward examples of their implementation.

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Hao, Fengjin, Yushu Ma, and Yifu Guan. "Effects of Central Loop Length and Metal Ions on the Thermal Stability of G-Quadruplexes." Molecules 24, no. 10 (May 15, 2019): 1863. http://dx.doi.org/10.3390/molecules24101863.

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The central loop of G-quadruplex molecular beacons is a key element to sense target DNA or RNA sequences. In this study, circular dichroism spectroscopy (CD), thermal difference spectrum (TDS), non-denatured non-denaturing gel electrophoresis, and thermal stability analysis were used to investigate the effect of the central loop length on G-quadruplex features. Two series of G-quadruplexes, AG3TTAG3-(TTA)n-G3TTAG3T (n = 1–8) (named TTA series) and AG3TTTG3-(TTA)n-G3TTTG3T (n = 1–8) (named TTT series) were examined in K+ and Na+ solutions, respectively. CD and TDS spectral data indicated that TTA series adopted an antiparallel G-quadruplex structure in Na+ solution and a hybrid G-quadruplex structure in K+ solution respectively. TTT series exhibited a hybrid G-quadruplex structure in both Na+ and K+ solutions. UV melting curves indicated that the stability of G-quadruplex in both series was reduced by the elongation of central loop. Thermal stability analysis concluded that the G-quadruplex destabilization with long central loop is an entropy-driven process due to more flexible and longer central loops.

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Chaires, Jonathan B., Robert D. Gray, William L. Dean, Robert Monsen, Lynn W. DeLeeuw, Vilius Stribinskis, and John O. Trent. "Human POT1 unfolds G-quadruplexes by conformational selection." Nucleic Acids Research 48, no. 9 (March 31, 2020): 4976–91. http://dx.doi.org/10.1093/nar/gkaa202.

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Abstract The reaction mechanism by which the shelterin protein POT1 (Protection of Telomeres 1) unfolds human telomeric G-quadruplex structures is not fully understood. We report here kinetic, thermodynamic, hydrodynamic and computational studies that show that a conformational selection mechanism, in which POT1 binding is coupled to an obligatory unfolding reaction, is the most plausible mechanism. Stopped-flow kinetic and spectroscopic titration studies, along with isothermal calorimetry, were used to show that binding of the single-strand oligonucleotide d[TTAGGGTTAG] to POT1 is both fast (80 ms) and strong (−10.1 ± 0.3 kcal mol−1). In sharp contrast, kinetic studies showed the binding of POT1 to an initially folded 24 nt G-quadruplex structure is four orders of magnitude slower. Fluorescence, circular dichroism and analytical ultracentrifugation studies showed that POT1 binding is coupled to quadruplex unfolding, with a final complex with a stoichiometry of 2 POT1 per 24 nt DNA. The binding isotherm for the POT1-quadruplex interaction was sigmoidal, indicative of a complex reaction. A conformational selection model that includes equilibrium constants for both G-quadruplex unfolding and POT1 binding to the resultant single-strand provided an excellent quantitative fit to the experimental binding data. POT1 unfolded and bound to any conformational form of human telomeric G-quadruplex (antiparallel, hybrid, parallel monomers or a 48 nt sequence with two contiguous quadruplexes), but did not avidly interact with duplex DNA or with other G-quadruplex structures. Finally, molecular dynamics simulations provided a detailed structural model of a 2:1 POT1:DNA complex that is fully consistent with experimental biophysical results.

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Scott, Lily, and Tigran V. Chalikian. "Stabilization of G-Quadruplex-Duplex Hybrid Structures Induced by Minor Groove-Binding Drugs." Life 12, no. 4 (April 18, 2022): 597. http://dx.doi.org/10.3390/life12040597.

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Once it had been realized that G-quadruplexes exist in the cell and are involved in regulation of genomic processes, the quest for ligands recognizing these noncanonical structures was underway. Many organic compounds that tightly associate with G-quadruplexes have been identified. However, the specificity of G-quadruplex-binding ligands towards individual structures remains problematic, as the common recognition element of these ligands is the G-tetrad. In this paper, we focus on G-quadruplex-duplex hybrids (QDH) containing a hairpin duplex incorporated as a stem-loop into the G-quadruplex core. The presence of a stem-loop renders QDH amenable to sequence-specific recognition by duplex-binding drugs. Should the thermodynamic crosstalk between the stem-loop and the tetraplex core be sufficiently strong, the drug binding to the loop would lead to the stabilization of the entire structure. We studied the stabilizing influence of the minor groove-binders netropsin and Hoechst 33258 on a family of QDH structures, as well as a G-quadruplex and a hairpin modeling the G-quadruplex core and the stem-loop of the QDH’s. We found that the binding of either drug results in an enhancement of the thermal stability of all DNA structures, as expressed by increases in the melting temperature, TM. Analysis of the hierarchical order of increases in TM revealed that the drug-induced stabilization arises from drug binding to the G-quadruplex domain of a QDH and the stem-loop, if the latter contains an all-AT binding site. This result attests to the thermodynamic crosstalk between the stem-loop and the tetraplex core of a QDH. Given the existing library of minor groove-binding drugs recognizing mixed A·T and G·C DNA sequences, our results point to an untapped avenue for sequence-specific recognition of QDH structures in vitro and, possibly, in vivo; thereby, opening the way for selective stabilization of four-stranded DNA structures at predetermined genomic loci, with implications for the control of genomic events.

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Fujimoto, Takeshi, Shu-ichi Nakano, Daisuke Miyoshi, and Naoki Sugimoto. "The Effects of Molecular Crowding on the Structure and Stability of G-Quadruplexes with an Abasic Site." Journal of Nucleic Acids 2011 (2011): 1–9. http://dx.doi.org/10.4061/2011/857149.

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Both cellular environmental factors and chemical modifications critically affect the properties of nucleic acids. However, the structure and stability of DNA containing abasic sites under cell-mimicking molecular crowding conditions remain unclear. Here, we investigated the molecular crowding effects on the structure and stability of the G-quadruplexes including a single abasic site. Structural analysis by circular dichroism showed that molecular crowding by PEG200 did not affect the topology of the G-quadruplex structure with or without an abasic site. Thermodynamic analysis further demonstrated that the degree of stabilization of the G-quadruplex by molecular crowding decreased with substitution of an abasic site for a single guanine. Notably, we found that the molecular crowding effects on the enthalpy change for G-quadruplex formation had a linear relationship with the abasic site effects depending on its position. These results are useful for predicting the structure and stability of G-quadruplexes with abasic sites in the cell-mimicking conditions.

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Gudanis, Dorota, Karolina Zielińska, Daniel Baranowski, Ryszard Kierzek, Piotr Kozłowski, and Zofia Gdaniec. "Impact of a Single Nucleotide Change or Non-Nucleoside Modifications in G-Rich Region on the Quadruplex–Duplex Hybrid Formation." Biomolecules 11, no. 8 (August 18, 2021): 1236. http://dx.doi.org/10.3390/biom11081236.

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In this paper, a method to discriminate between two target RNA sequences that differ by one nucleotide only is presented. The method relies on the formation of alternative structures, i.e., quadruplex–duplex hybrid (QDH) and duplex with dangling ends (Dss), after hybridization of DNA or RNA G-rich oligonucleotides with target sequences containing 5′–GGGCUGG–3′ or 5′–GGGCGGG–3′ fragments. Using biophysical methods, we studied the effect of oligonucleotide types (DNA, RNA), non-nucleotide modifications (aliphatic linkers or abasic), and covalently attached G4 ligand on the ability of G-rich oligonucleotides to assemble a G-quadruplex motif. We demonstrated that all examined non-nucleotide modifications could mimic the external loops in the G-quadruplex domain of QDH structures without affecting their stability. Additionally, some modifications, in particular the presence of two abasic residues in the G-rich oligonucleotide, can induce the formation of non-canonical QDH instead of the Dss structure upon hybridization to a target sequence containing the GGGCUGG motif. Our results offer new insight into the sequential requirements for the formation of G-quadruplexes and provide important data on the effects of non-nucleotide modifications on G-quadruplex formation.

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Ishizuka, Takumi, Pei-Yan Zhao, Hong-Liang Bao, and Yan Xu. "A multi-functional guanine derivative for studying the DNA G-quadruplex structure." Analyst 142, no. 21 (2017): 4083–88. http://dx.doi.org/10.1039/c7an00941k.

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A multi-functional guanine derivative, ^8FG, as a G-quadruplex stabilizer, a fluorescent probe for the detection of G-quadruplex formation, and a ¹⁹F sensor for the observation of the G-quadruplex in vitro and in living cells.

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Roxo, Carolina, Weronika Kotkowiak, and Anna Pasternak. "G-Quadruplex-Forming Aptamers—Characteristics, Applications, and Perspectives." Molecules 24, no. 20 (October 21, 2019): 3781. http://dx.doi.org/10.3390/molecules24203781.

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G-quadruplexes constitute a unique class of nucleic acid structures formed by G-rich oligonucleotides of DNA- or RNA-type. Depending on their chemical nature, loops length, and localization in the sequence or structure molecularity, G-quadruplexes are highly polymorphic structures showing various folding topologies. They may be formed in the human genome where they are believed to play a pivotal role in the regulation of multiple biological processes such as replication, transcription, and translation. Thus, natural G-quadruplex structures became prospective targets for disease treatment. The fast development of systematic evolution of ligands by exponential enrichment (SELEX) technologies provided a number of G-rich aptamers revealing the potential of G-quadruplex structures as a promising molecular tool targeted toward various biologically important ligands. Because of their high stability, increased cellular uptake, ease of chemical modification, minor production costs, and convenient storage, G-rich aptamers became interesting therapeutic and diagnostic alternatives to antibodies. In this review, we describe the recent advances in the development of G-quadruplex based aptamers by focusing on the therapeutic and diagnostic potential of this exceptional class of nucleic acid structures.

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Zhang, Yun, Xinao Ma, Jingtian Zhang, Feixian Luo, Wenshu Wang, and Xiaojie Cui. "Design of a High-Sensitivity Dimeric G-Quadruplex/Hemin DNAzyme Biosensor for Norovirus Detection." Molecules 26, no. 23 (December 3, 2021): 7352. http://dx.doi.org/10.3390/molecules26237352.

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G-quadruplexes can bind with hemin to form peroxidase-like DNAzymes that are widely used in the design of biosensors. However, the catalytic activity of G-quadruplex/hemin DNAzyme is relatively low compared with natural peroxidase, which hampers its sensitivity and, thus, its application in the detection of nucleic acids. In this study, we developed a high-sensitivity biosensor targeting norovirus nucleic acids through rationally introducing a dimeric G-quadruplex structure into the DNAzyme. In this strategy, two separate molecular beacons each having a G-quadruplex-forming sequence embedded in the stem structure are brought together through hybridization with a target DNA strand, and thus forms a three-way junction architecture and allows a dimeric G-quadruplex to form, which, upon binding with hemin, has a synergistic enhancement of catalytic activities. This provides a high-sensitivity colorimetric readout by the catalyzing H2O2-mediated oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline -6-sulfonic acid) diammonium salt (ABTS). Up to 10 nM of target DNA can be detected through colorimetric observation with the naked eye using our strategy. Hence, our approach provides a non-amplifying, non-labeling, simple-operating, cost-effective colorimetric biosensing method for target nucleic acids, such as norovirus-conserved sequence detection, and highlights the further implication of higher-order multimerized G-quadruplex structures in the design of high-sensitivity biosensors.

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Zou, Liyuan, Hongbo Li, Mingbin Liu, Weihua Zhao, and Suqin Wang. "Enhancement Effect of Zn-Arsenazo III Complex for G-quadruplex DNA Stability of Proto-oncogene Promoter Telomeres." Letters in Drug Design & Discovery 17, no. 7 (July 6, 2020): 858–66. http://dx.doi.org/10.2174/1570180816666191112154141.

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Background: Controlling the structure of proto-oncogene telomeres is very important in antitumor therapy. There are relationships between G-quadruplex DNA and the growth of tumor cell. Methods: In this study, spectroscopic, cyclic voltammetry and viscosity methods were employed to investigate the interaction between Zn-Arsenazo Ⅲ complex and G-quadruplex DNA by using 4S Green Plus Nucleic Acid Stain as a spectral probe in PBS buffer. The binding ratios were n Arsenazo Ⅲ : n Zn(Ⅱ) = 5:1 for Zn-Arsenazo Ⅲ complex and n Zn- Arsenazo Ⅲ : n G-quadruplex DNA = 8:1 for Zn-Arsenazo Ⅲ-G-quadruplex DNA. The bonding constants (Kθ 298.15K=4.44x105 L·mol-1, Kθ 308.15K= 1.00x105 L·mol-1, Kθ 318.15K= 1.04x106 L·mol-1) were obtained by double reciprocal method at different temperatures, Which was found that the interaction between Zn-Arsenazo Ⅲ complex and Gquadruplex DNA was driven by enthalpy. Furthermore, the research further confirmed that the interaction mode between Zn-Arsenazo Ⅲ complex and G-quadruplex DNA was a mixed binding which involved intercalation and non-intercalation interaction. Results and Conclusion: Together these findings also have corroborated the application of stabilizing ligands and intervening with their function for target G-quadruplexes in a cellular context.

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König, Sebastian L. B., Amanda C. Evans, and Julian L. Huppert. "Seven essential questions on G-quadruplexes." BioMolecular Concepts 1, no. 2 (August 1, 2010): 197–213. http://dx.doi.org/10.1515/bmc.2010.011.

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AbstractThe helical duplex architecture of DNA was discovered by Francis Crick and James Watson in 1951 and is well known and understood. However, nucleic acids can also adopt alternative structural conformations that are less familiar, although no less biologically relevant, such as the G-quadruplex. G-quadruplexes continue to be the subject of a rapidly expanding area of research, owing to their significant potential as therapeutic targets and their unique biophysical properties. This review begins by focusing on G-quadruplex structure, elucidating the intermolecular and intramolecular interactions underlying its formation and highlighting several substructural variants. A variety of methods used to characterize these structures are also outlined. The current state of G-quadruplex research is then addressed by proffering seven pertinent questions for discussion. This review concludes with an overview of possible directions for future research trajectories in this exciting and relevant field.

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Adeoye, Raphael I., Dunsin S. Osalaye, Theresia K. Ralebitso-Senior, Amanda Boddis, Amanda J. Reid, Amos A. Fatokun, Andrew K. Powell, Sylvia O. Malomo, and Femi J. Olorunniji. "Catalytic Activities of Multimeric G-Quadruplex DNAzymes." Catalysts 9, no. 7 (July 19, 2019): 613. http://dx.doi.org/10.3390/catal9070613.

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G-quadruplex DNAzymes are short DNA aptamers with repeating G4 quartets bound in a non-covalent complex with hemin. These G4/Hemin structures exhibit versatile peroxidase-like catalytic activity with a wide range of potential applications in biosensing and biotechnology. Current efforts are aimed at gaining a better understanding of the molecular mechanism of DNAzyme catalysis as well as devising strategies for improving their catalytic efficiency. Multimerisation of discrete units of G-quadruplexes to form multivalent DNAzyes is an emerging design strategy aimed at enhancing the peroxidase activities of DNAzymes. While this approach holds promise of generating more active multivalent G-quadruplex DNAzymes, few examples have been studied and it is not clear what factors determine the enhancement of catalytic activities of multimeric DNAzymes. In this study, we report the design and characterisation of multimers of five G-quadruplex sequences (AS1411, Bcl-2, c-MYC, PS5.M and PS2.M). Our results show that multimerisation of G-quadruplexes that form parallel structure (AS1411, Bcl-2, c-MYC) leads to significant rate enhancements characteristic of cooperative and/or synergistic interactions between the monomeric units. In contrast, multimerisation of DNA sequences that form non-parallel structures (PS5.M and PS2.M) did not exhibit similar levels of synergistic increase in activities. These results show that design of multivalent G4/Hemin structures could lead to a new set of versatile and efficient DNAzymes with enhanced capacity to catalyse peroxidase-mimic reactions.

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Bizyaeva, Anastasia A., Dmitry A. Bunin, Valeria L. Moiseenko, Alexandra S. Gambaryan, Sonja Balk, Vadim N. Tashlitsky, Alexander M. Arutyunyan, Alexey M. Kopylov, and Elena G. Zavyalova. "The Functional Role of Loops and Flanking Sequences of G-Quadruplex Aptamer to the Hemagglutinin of Influenza a Virus." International Journal of Molecular Sciences 22, no. 5 (February 27, 2021): 2409. http://dx.doi.org/10.3390/ijms22052409.

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Nucleic acid aptamers are generally accepted as promising elements for the specific and high-affinity binding of various biomolecules. It has been shown for a number of aptamers that the complexes with several related proteins may possess a similar affinity. An outstanding example is the G-quadruplex DNA aptamer RHA0385, which binds to the hemagglutinins of various influenza A virus strains. These hemagglutinins have homologous tertiary structures but moderate-to-low amino acid sequence identities. Here, the experiment was inverted, targeting the same protein using a set of related, parallel G-quadruplexes. The 5′- and 3′-flanking sequences of RHA0385 were truncated to yield parallel G-quadruplex with three propeller loops that were 7, 1, and 1 nucleotides in length. Next, a set of minimal, parallel G-quadruplexes with three single-nucleotide loops was tested. These G-quadruplexes were characterized both structurally and functionally. All parallel G-quadruplexes had affinities for both recombinant hemagglutinin and influenza virions. In summary, the parallel G-quadruplex represents a minimal core structure with functional activity that binds influenza A hemagglutinin. The flanking sequences and loops represent additional features that can be used to modulate the affinity. Thus, the RHA0385–hemagglutinin complex serves as an excellent example of the hypothesis of a core structure that is decorated with additional recognizing elements capable of improving the binding properties of the aptamer.

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Prakash, Aishwarya, Fabien Kieken, Luis A. Marky, and Gloria E. O. Borgstahl. "Stabilization of a G-Quadruplex from Unfolding by Replication Protein A Using Potassium and the Porphyrin TMPyP4." Journal of Nucleic Acids 2011 (2011): 1–13. http://dx.doi.org/10.4061/2011/529828.

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Replication protein A (RPA) plays an essential role in DNA replication by binding and unfolding non-canonical single-stranded DNA (ssDNA) structures. Of the six RPA ssDNA binding domains (labeled A-F), RPA-CDE selectively binds a G-quadruplex forming sequence (5′-TAGGGGAAGGGTTGGAGTGGGTT-3′called Gq23). In K+, Gq23 forms a mixed parallel/antiparallel conformation, and in Na+Gq23 has a less stable (TMlowered by ∼20∘C), antiparallel conformation. Gq23 is intramolecular and 1D NMR confirms a stable G-quadruplex structure in K+. Full-length RPA and RPA-CDE-core can bind and unfold the Na+form of Gq23 very efficiently, but complete unfolding is not observed with the K+form. Studies with G-quadruplex ligands, indicate that TMPyP4 has a thermal stabilization effect on Gq23 in K+, and inhibits complete unfolding by RPA and RPA-CDE-core. Overall these data indicate that G-quadruplexes present a unique problem for RPA to unfold and ligands, such as TMPyP4, could possibly hinder DNA replication by blocking unfolding by RPA.

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Gómez-Márquez, Jaime. "DNA G-quadruplex: structure, function and human disease." FEBS Journal 277, no. 17 (July 29, 2010): 3451. http://dx.doi.org/10.1111/j.1742-4658.2010.07757.x.

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Morel, Elodie, Claire Beauvineau, Delphine Naud-Martin, Corinne Landras-Guetta, Daniela Verga, Deepanjan Ghosh, Sylvain Achelle, Florence Mahuteau-Betzer, Sophie Bombard, and Marie-Paule Teulade-Fichou. "Selectivity of Terpyridine Platinum Anticancer Drugs for G-quadruplex DNA." Molecules 24, no. 3 (January 23, 2019): 404. http://dx.doi.org/10.3390/molecules24030404.

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Guanine-rich DNA can form four-stranded structures called G-quadruplexes (G4s) that can regulate many biological processes. Metal complexes have shown high affinity and selectivity toward the quadruplex structure. Here, we report the comparison of a panel of platinum (II) complexes for quadruplex DNA selective recognition by exploring the aromatic core around terpyridine derivatives. Their affinity and selectivity towards G4 structures of various topologies have been evaluated by FRET-melting (Fluorescence Resonance Energy Transfert-melting) and Fluorescent Intercalator Displacement (FID) assays, the latter performed by using three different fluorescent probes (Thiazole Orange (TO), TO-PRO-3, and PhenDV). Their ability to bind covalently to the c-myc G4 structure in vitro and their cytotoxicity potential in two ovarian cancerous cell lines were established. Our results show that the aromatic surface of the metallic ligands governs, in vitro, their affinity, their selectivity for the G4 over the duplex structures, and platination efficiency. However, the structural modifications do not allow significant discrimination among the different G4 topologies. Moreover, all compounds were tested on ovarian cancer cell lines and normal cell lines and were all able to overcome cisplatin resistance highlighting their interest as new anticancer drugs.

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Nagesh, Narayana, Varun K. Sharma, A. Ganesh Kumar, and Edwin A. Lewis. "Effect of Ionic Strength on Porphyrin Drugs Interaction with Quadruplex DNA Formed by the Promoter Region of C-myc and Bcl2 Oncogenes." Journal of Nucleic Acids 2010 (2010): 1–9. http://dx.doi.org/10.4061/2010/146418.

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C-myc and Bcl2 are well characterized oncogenes that are capable of forming G-quadruplex structures. Promoter regions of C-myc and Bcl2 forming G-quadruplex structures are chemically synthesized and G-quadruplex structure is formed in presence of 100 mM potassium ion. Three different porphyrin drugs, namely TMPyP2, TMPyP3, and TMPyP4 are allowed to interact with quadruplex DNA complex and the site and nature of interaction are studied. Drug interactions with quadruplex DNA were carried out in different potassium ionic strengths using fluorescence spectroscopy. It is found that fluorescence hypochromicity decreases with an increase in ionic strength in the case of TMPyP4, TMPyP3, and TMPyP2. Fluorescence titration studies and Job plots indicate that four molecules of TMPyP4, two molecules of TMPyP3 and TMPyP2 are interacting with one molecule of quadruplex DNA.

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Ramos, Catarina, Susana Almeida, Leandro Lourenço, Patrícia Pereira, Rosa Fernandes, M. Faustino, João Tomé, Josué Carvalho, Carla Cruz, and M. Neves. "Multicharged Phthalocyanines as Selective Ligands for G-Quadruplex DNA Structures." Molecules 24, no. 4 (February 18, 2019): 733. http://dx.doi.org/10.3390/molecules24040733.

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The stabilization of G-Quadruplex DNA structures by ligands is a promising strategy for telomerase inhibition in cancer therapy since this enzyme is responsible for the unlimited proliferation of cancer cells. To assess the potential of a compound as a telomerase inhibitor, selectivity for quadruplex over duplex DNA is a fundamental attribute, as the drug must be able to recognize quadruplex DNA in the presence of a large amount of duplex DNA, in the cellular nucleus. By using different spectroscopic techniques, such as ultraviolet-visible, fluorescence and circular dichroism, this work evaluates the potential of a series of multicharged phthalocyanines, bearing four or eight positive charges, as G-Quadruplex stabilizing ligands. This work led us to conclude that the existence of a balance between the number and position of the positive charges in the phthalocyanine structure is a fundamental attribute for its selectivity for G-Quadruplex structures over duplex DNA structures. Two of the studied phthalocyanines, one with four peripheral positive charges (ZnPc1) and the other with less exposed eight positive charges (ZnPc4) showed high selectivity and affinity for G-Quadruplex over duplex DNA structures and were able to accumulate in the nucleus of UM-UC-3 bladder cancer cells.

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Livendahl, M., J. Jamroskovic, M. Hedenström, T. Görlich, N. Sabouri, and E. Chorell. "Synthesis of phenanthridine spiropyrans and studies of their effects on G-quadruplex DNA." Organic & Biomolecular Chemistry 15, no. 15 (2017): 3265–75. http://dx.doi.org/10.1039/c7ob00300e.

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Roxo, Carolina, and Anna Pasternak. "Changes in physicochemical and anticancer properties modulated by chemically modified sugar moieties within sequence-related G-quadruplex structures." PLOS ONE 17, no. 8 (August 23, 2022): e0273528. http://dx.doi.org/10.1371/journal.pone.0273528.

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We systematically investigated the influence of locked nucleic acid (LNA), unlock nucleic acid (UNA), and 2’-O-methyl-RNA (2’-O-Me-RNA) residues on the thermal stability, structure folding topology, biological activity and enzymatic resistance of three sequence-related DNA G-quadruplexes. In order to better understand the mechanism of action of the studied modifications, a single-position substitution in the loops or G-tetrads was performed and their influence was analyzed for a total of twenty-seven modified G-quadruplex variants. The studies show that the influence of each modification on the physicochemical properties of G-quadruplexes is position-dependent, due to mutual interactions between G-tetrads, loops, and additional guanosine at 5’ or 3’ end. Nevertheless, the anticancer activity of the modified G-quadruplexes is determined by their structure, thus also by the local changes of chemical character of sugar moieties, what might influence the specific interactions with therapeutic targets. In general, UNA modifications are efficient modulators of the G-quadruplex thermodynamic stability, however they are poor tools to improve the anticancer properties. In contrast, LNA and 2’-O-Me-RNA modified G-quadruplexes demonstrated certain antiproliferative potential and might be used as molecular tools for designing novel G-quadruplex-based therapeutics.

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Sowers, Mark L., James W. Conrad, Bruce Chang-Gu, Ellie Cherryhomes, Linda C. Hackfeld, and Lawrence C. Sowers. "DNA Base Excision Repair Intermediates Influence Duplex–Quadruplex Equilibrium." Molecules 28, no. 3 (January 18, 2023): 970. http://dx.doi.org/10.3390/molecules28030970.

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Although genomic DNA is predominantly duplex under physiological conditions, particular sequence motifs can favor the formation of alternative secondary structures, including the G-quadruplex. These structures can exist within gene promoters, telomeric DNA, and regions of the genome frequently found altered in human cancers. DNA is also subject to hydrolytic and oxidative damage, and its local structure can influence the type of damage and its magnitude. Although the repair of endogenous DNA damage by the base excision repair (BER) pathway has been extensively studied in duplex DNA, substantially less is known about repair in non-duplex DNA structures. Therefore, we wanted to better understand the effect of DNA damage and repair on quadruplex structure. We first examined the effect of placing pyrimidine damage products uracil, 5-hydroxymethyluracil, the chemotherapy agent 5-fluorouracil, and an abasic site into the loop region of a 22-base telomeric repeat sequence known to form a G-quadruplex. Quadruplex formation was unaffected by these analogs. However, the activity of the BER enzymes were negatively impacted. Uracil DNA glycosylase (UDG) and single-strand selective monofunctional uracil DNA glycosylase (SMUG1) were inhibited, and apurinic/apyrimidinic endonuclease 1 (APE1) activity was completely blocked. Interestingly, when we performed studies placing DNA repair intermediates into the strand opposite the quadruplex, we found that they destabilized the duplex and promoted quadruplex formation. We propose that while duplex is the preferred configuration, there is kinetic conversion between duplex and quadruplex. This is supported by our studies using a quadruplex stabilizing molecule, pyridostatin, that is able to promote quadruplex formation starting from duplex DNA. Our results suggest how DNA damage and repair intermediates can alter duplex-quadruplex equilibrium.

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Li, Dawei, Peiwen Peng, Zhaoqi Yang, and Bei Lv. "Formation of G-quadruplex structure in supercoiled DNA under molecularly crowded conditions." RSC Advances 9, no. 45 (2019): 26248–51. http://dx.doi.org/10.1039/c9ra06370f.

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It is demonstrated that G-quadruplex generated from G-rich duplex in a circular DNA as a result of quadruplex stabilization and duplex destabilization created by the combined actions of negative DNA supercoiling and molecular crowding condition.

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Onizuka, Kazumitsu, Erchissaran Ganbold, Yue Ma, Shogo Sasaki, Madoka E. Hazemi, Yutong Chen, Norihiro Sato, Mamiko Ozawa, Kazuo Nagasawa, and Fumi Nagatsugi. "Selective alkylation of parallel G-quadruplex structure." Organic & Biomolecular Chemistry 19, no. 13 (2021): 2891–94. http://dx.doi.org/10.1039/d0ob02365e.

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Takahashi, Shuntaro, Sudipta Bhowmik, Shinobu Sato, Shigeori Takenaka, and Naoki Sugimoto. "Replication Control of Human Telomere G-Quadruplex DNA by G-Quadruplex Ligands Dependent on Solution Environment." Life 12, no. 4 (April 7, 2022): 553. http://dx.doi.org/10.3390/life12040553.

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The human telomere region is known to contain guanine-rich repeats and form a guanine-quadruplex (G4) structure. As telomeres play a role in the regulation of cancer progression, ligands that specifically bind and stabilize G4 have potential therapeutic applications. However, as the human telomere sequence can form G4 with various topologies due to direct interaction by ligands and indirect interaction by the solution environment, it is of great interest to study the topology-dependent control of replication by ligands. In the present study, a DNA replication assay of a template with a human telomere G4 sequence in the presence of various ligands was performed. Cyclic naphthalene diimides (cNDI1 and cNDI2) efficiently increased the replication stall of the template DNA at G4 with an anti-parallel topology. This inhibition was stability-dependent and topology-selective, as the replication of templates with hybrid or parallel G4 structures was not affected by the cNDI and cNDI2. Moreover, the G4 ligand fisetin repressed replication with selectivity for anti-parallel and hybrid G4 structures without stabilization. Finally, the method used, referred to as quantitative study of topology-dependent replication (QSTR), was adopted to evaluate the correlation between the replication kinetics and the stability of G4. Compared to previous results obtained using a modified human telomere sequence, the relationship between the stability of G4 and the effect on the topology-dependent replication varied. Our results suggest that native human telomere G4 is more flexible than the modified sequence for interacting with ligands. These findings indicate that the modification of the human telomeric sequence forces G4 to rigidly form a specific structure of G4, which can restrict the change in topology-dependent replication by some ligands.

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Honisch, Claudia, Eugenio Ragazzi, Rohanah Hussain, John Brazier, Giuliano Siligardi, and Paolo Ruzza. "Interaction of a Short Peptide with G-Quadruplex-Forming Sequences: An SRCD and CD Study." Pharmaceutics 13, no. 8 (July 21, 2021): 1104. http://dx.doi.org/10.3390/pharmaceutics13081104.

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G-quadruplex (G4) forming DNA sequences were recently found to play a crucial role in the regulation of genomic processes such as replication, transcription and translation, also related to serious diseases. Therefore, systems capable of controlling DNA and RNA G-quadruplex structures would be useful for the modulation of various cellular events. In particular, peptides represent good candidates for targeting G-quadruplex structures, since they are easily tailored to enhance their functionality. In this work, we analyzed, by circular dichroism and synchrotron radiation circular dichroism spectroscopies, the interaction of a 25-residue peptide deriving from RHAU helicases (Rhau25) with three G-quadruplex-forming oligonucleotide sequences, in both sodium- and potassium-containing buffers, the most relevant monovalent cations in physiological conditions. The peptide displayed greater affinity for the G4 sequences adopting a parallel structure. However, it showed the ability to also interact with antiparallel or hybrid G-quadruplex structures, inducing a conformation conversion to the parallel structure. The stability of the oligonucleotide structure alone or in presence of the Rhau25 peptide was studied by temperature melting and UV denaturation experiments, and the data showed that the interaction with the peptide stabilized the conformation of oligonucleotide sequences when subjected to stress conditions.

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Liu, Gui Lin, Yan Ping Ding, Yan Ling Wu, and Wen Zhang. "Research Progress in the Typical Structure of Human Telomeric G-Quadruplex." Advanced Materials Research 955-959 (June 2014): 419–22. http://dx.doi.org/10.4028/www.scientific.net/amr.955-959.419.

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Telomeric DNA of human chromosomes plays a significant role in physiological processes such as cell cycle, aging, cancer and genetic stability due to its special sequence and structure. The research on small molecule ligands targeting G-quadruplex formed by such special sequence has attracted considerable attention, and has achieved great breakthrough. In this paper, we summarize the DNA sequences and structures of three kinds of typical human telomeric G-quadruplex, providing an important reference for further research.

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Kim, Seyeon, and Jongback Gang. "Label-free simple fluorescence assay of DNA polymerase using the G-quadruplex structure." Analytical Methods 8, no. 2 (2016): 275–79. http://dx.doi.org/10.1039/c5ay02379c.

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In this study, the G-quadruplex structure was used to detect the enzymatic activity and inhibition of the Klenow fragment exo⁻(KF⁻) in the presence ofN-methylmesoporphyrin IX (NMM) which binds specifically to the G-quadruplex.

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Do, Ngoc Quang, Wan Jun Chung, Thi Hong Anh Truong, Brahim Heddi, and Anh Tuân Phan. "G-quadruplex structure of an anti-proliferative DNA sequence." Nucleic Acids Research 45, no. 12 (May 26, 2017): 7487–93. http://dx.doi.org/10.1093/nar/gkx274.

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Zhou, Hui, Zai-Sheng Wu, Guo-Li Shen, and Ru-Qin Yu. "Intermolecular G-quadruplex structure-based fluorescent DNA detection system." Biosensors and Bioelectronics 41 (March 2013): 262–67. http://dx.doi.org/10.1016/j.bios.2012.08.028.

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Wang, Yong, and Dinshaw J. Patel. "Solution Structure of a Parallel-stranded G-Quadruplex DNA." Journal of Molecular Biology 234, no. 4 (December 1993): 1171–83. http://dx.doi.org/10.1006/jmbi.1993.1668.

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Pagano, Bruno, Luigi Margarucci, Pasquale Zizza, Jussara Amato, Nunzia Iaccarino, Chiara Cassiano, Erica Salvati, et al. "Identification of novel interactors of human telomeric G-quadruplex DNA." Chemical Communications 51, no. 14 (2015): 2964–67. http://dx.doi.org/10.1039/c4cc07231f.

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Starting from a chemoproteomic-driven approach, novel human telomeric G-quadruplex binding proteins were identified that directly bind the DNA structure in vitro and colocalize with such structures in cells.

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Kim, Nayun. "The Interplay between G-quadruplex and Transcription." Current Medicinal Chemistry 26, no. 16 (August 26, 2019): 2898–917. http://dx.doi.org/10.2174/0929867325666171229132619.

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G4 DNA is a non-canonical DNA structure consisting of a stacked array of Gquartets held together by base pairing between guanine bases. The formation of G4 DNA requires a cluster of guanine-runs within a strand of DNA. Even though the chemistry of this remarkable DNA structure has been under investigation for decades, evidence supporting the biological relevance of G4 DNA has only begun to emerge and point to very important and conserved biological functions. This review will specifically focus on the interplay between transcription and G4 DNA and discuss two alternative but interconnected perspectives. The first part of the review will describe the evidence substantiating the intriguing idea that a shift in DNA structural conformation could be another layer of non-genetic or epigenetic regulator of gene expression and thereby an important determinant of cell fate. The second part will describe the recent genetic studies showing that those genomic loci containing G4 DNA-forming guanine-rich sequences are potential hotspots of genome instability and that the level and orientation of transcription is critical in the materialization of genome instability associated with these sequences.

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Li, Zi Jian, Yan Ping Ding, Su Lin Zhang, Yan Ling Wu, and Wen Zhang. "Small Natural Molecules Targeting DNA G-Quadruplexes." Advanced Materials Research 955-959 (June 2014): 423–26. http://dx.doi.org/10.4028/www.scientific.net/amr.955-959.423.

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DNA G-quadruplex (G4-DNA) has emerged as a new drug target for anti-tumor. The small compounds can induce the formation of G4-DNA and stabilize its structures, which is of potential significance for the tumor treatment. This paper focuses on our current understanding about the structure of G4-DNA, the binding mode between G4-DNA and small molecular ligands, and natural products targeting G4-DNA.

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Bryan, Tracy M. "Mechanisms of DNA Replication and Repair: Insights from the Study of G-Quadruplexes." Molecules 24, no. 19 (September 22, 2019): 3439. http://dx.doi.org/10.3390/molecules24193439.

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G-quadruplexes are four-stranded guanine-rich structures that have been demonstrated to occur across the genome in humans and other organisms. They provide regulatory functions during transcription, translation and immunoglobulin gene rearrangement, but there is also a large amount of evidence that they can present a potent barrier to the DNA replication machinery. This mini-review will summarize recent advances in understanding the many strategies nature has evolved to overcome G-quadruplex-mediated replication blockage, including removal of the structure by helicases or nucleases, or circumventing the deleterious effects on the genome through homologous recombination, alternative end-joining or synthesis re-priming. Paradoxically, G-quadruplexes have also recently been demonstrated to provide a positive role in stimulating the initiation of DNA replication. These recent studies have not only illuminated the many roles and consequences of G-quadruplexes, but have also provided fundamental insights into the general mechanisms of DNA replication and its links with genetic and epigenetic stability.

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Journal articles on the topic 'DNA, G-quadruplex, structure'

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