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1
Han, Ji Ho, and Moon Jung Song. "인간 허피스바이러스에 대한 G-quadruplex 결합 리간드의 항바이러스 효과." Institute of Life Science and Natural Resources 30 (December 31, 2022): 23–31. http://dx.doi.org/10.33147/lsnrr.2022.30.1.23.
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G-quadruplexes (G4s) are noncanonical secondary nucleic acid structures constituted by stacking of guanine rich planar shaped tetrad formations that form a complex. G4s are implicated for various important roles in key cellular processes transcription, translation, telomere maintenance, epigenetic regulation, replication, and recombination. G-quadruplexes were first discovered as important structures in oncology, but for the past decade its relevance in viruses is becoming more evident. Human herpesviruses are DNA viruses of the Herpesviridae family and are unique in characteristic with two types of infection which can be distinguished by lytic and latency establishment in the host. During latency the virus maintains lifelong dormancy and intermittently undergoes reactivation, causing the host medical problems. Recently there are increasing number of reports regarding role of G4s in viral genomes and the potential antiviral efficacy of G4 ligands, including G4s in latency. Many results suggest viral G4s play significant roles in the virus life cycle and treatment of G4 ligands exhibit antiviral activities in both lytic and latent infections. In this review, the importance of G4s in herpesvirus genomes will be introduced with the potent G4 ligands used to study these mechanisms and finally explain the distinct functional properties of each G4 ligands.
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Artusi, Sara, Emanuela Ruggiero, Matteo Nadai, Beatrice Tosoni, Rosalba Perrone, Annalisa Ferino, Irene Zanin, Luigi Xodo, Louis Flamand, and Sara N. Richter. "Antiviral Activity of the G-Quadruplex Ligand TMPyP4 against Herpes Simplex Virus-1." Viruses 13, no. 2 (January 28, 2021): 196. http://dx.doi.org/10.3390/v13020196.
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The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.
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Nobile, C., J. Nickol, and R. G. Martin. "Nucleosome phasing on a DNA fragment from the replication origin of simian virus 40 and rephasing upon cruciform formation of the DNA." Molecular and Cellular Biology 6, no. 8 (August 1986): 2916–22. http://dx.doi.org/10.1128/mcb.6.8.2916-2922.1986.
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Nucleosomes were reconstituted in vitro from a fragment of DNA spanning the simian virus 40 minimal replication origin. The fragment contains a 27-base-pair palindrome (perfect inverted repeat). DNA molecules with stable cruciform structures were generated by heteroduplexing this DNA fragment with mutants altered within the palindromic sequence (C. Nobile and R. G. Martin, Int. Virol., in press). Analyses of the structural features of the reconstituted nucleosomes by the DNase I footprint technique revealed two alternative DNA-histone arrangements, each one accurately phased with respect to the uniquely labeled DNA ends. As linear double-stranded DNA, a unique core particle was formed in which the histones strongly protected the regions to both sides of the palindrome. The cruciform structure seemed to be unable to associate with core histones and, therefore, an alternative phasing of the histone octamer along the DNA resulted. Thus, nucleosome positioning along a specific DNA sequence appears to be influenced in vitro by the secondary structure (linear or cruciform) of the 27-base-pair palindrome. The formation of cruciform structures in vivo, if they occur, might therefore represent a molecular mechanism by which nucleosomes are phased.
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Nobile, C., J. Nickol, and R. G. Martin. "Nucleosome phasing on a DNA fragment from the replication origin of simian virus 40 and rephasing upon cruciform formation of the DNA." Molecular and Cellular Biology 6, no. 8 (August 1986): 2916–22. http://dx.doi.org/10.1128/mcb.6.8.2916.
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Nucleosomes were reconstituted in vitro from a fragment of DNA spanning the simian virus 40 minimal replication origin. The fragment contains a 27-base-pair palindrome (perfect inverted repeat). DNA molecules with stable cruciform structures were generated by heteroduplexing this DNA fragment with mutants altered within the palindromic sequence (C. Nobile and R. G. Martin, Int. Virol., in press). Analyses of the structural features of the reconstituted nucleosomes by the DNase I footprint technique revealed two alternative DNA-histone arrangements, each one accurately phased with respect to the uniquely labeled DNA ends. As linear double-stranded DNA, a unique core particle was formed in which the histones strongly protected the regions to both sides of the palindrome. The cruciform structure seemed to be unable to associate with core histones and, therefore, an alternative phasing of the histone octamer along the DNA resulted. Thus, nucleosome positioning along a specific DNA sequence appears to be influenced in vitro by the secondary structure (linear or cruciform) of the 27-base-pair palindrome. The formation of cruciform structures in vivo, if they occur, might therefore represent a molecular mechanism by which nucleosomes are phased.
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McDaniel, Yumeng Z., Dake Wang, Robin P. Love, Madison B. Adolph, Nazanin Mohammadzadeh, Linda Chelico, and Louis M. Mansky. "Deamination hotspots among APOBEC3 family members are defined by both target site sequence context and ssDNA secondary structure." Nucleic Acids Research 48, no. 3 (January 16, 2020): 1353–71. http://dx.doi.org/10.1093/nar/gkz1164.
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Abstract The human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3, A3) family member proteins can deaminate cytosines in single-strand (ss) DNA, which restricts human immunodeficiency virus type 1 (HIV-1), retrotransposons, and other viruses such as hepatitis B virus, but can cause a mutator phenotype in many cancers. While structural information exists for several A3 proteins, the precise details regarding deamination target selection are not fully understood. Here, we report the first parallel, comparative analysis of site selection of A3 deamination using six of the seven purified A3 member enzymes, oligonucleotides having 5′TC3′ or 5′CT3′ dinucleotide target sites, and different flanking bases within diverse DNA secondary structures. A3A, A3F and A3H were observed to have strong preferences toward the TC target flanked by A or T, while all examined A3 proteins did not show a preference for a TC target flanked by a G. We observed that the TC target was strongly preferred in ssDNA regions rather than dsDNA, loop or bulge regions, with flanking bases influencing the degree of preference. CT was also shown to be a potential deamination target. Taken together, our observations provide new insights into A3 enzyme target site selection and how A3 mutagenesis impacts mutation rates.
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Kopp, Martina, Harald Granzow, Walter Fuchs, Barbara G. Klupp, Egbert Mundt, Axel Karger, and Thomas C. Mettenleiter. "The Pseudorabies Virus UL11 Protein Is a Virion Component Involved in Secondary Envelopment in the Cytoplasm." Journal of Virology 77, no. 9 (May 1, 2003): 5339–51. http://dx.doi.org/10.1128/jvi.77.9.5339-5351.2003.
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ABSTRACT Homologs of the small tegument protein encoded by the UL11 gene of herpes simplex virus type 1 are conserved throughout all herpesvirus subfamilies. However, their function during viral replication has not yet been conclusively shown. Using a monospecific antiserum and an appropriate viral deletion and rescue mutant, we identified and functionally characterized the UL11 protein of the alphaherpesvirus pseudorabies virus (PrV). PrV UL11 encodes a protein with an apparent molecular mass of 10 to 13 kDa that is primarily detected at cytoplasmic membranes during viral replication. In the absence of the UL11 protein, viral titers were decreased approximately 10-fold and plaque sizes were reduced by 60% compared to wild-type virus. Intranuclear capsid maturation and nuclear egress resulting in translocation of DNA-containing capsids into the cytoplasm were not detectably affected. However, in the absence of the UL11 protein, intracytoplasmic membranes were distorted. Moreover, in PrV-ΔUL11-infected cells, capsids accumulated in the cytoplasm and were often found associated with tegument in aggregated structures such as had previously been demonstrated in cells infected with a PrV triple-mutant virus lacking glycoproteins E, I, and M (A. R. Brack, J. M. Dijkstra, H. Granzow, B. G. Klupp, and T. C. Mettenleiter, J. Virol. 73:5364-5372, 1999). Thus, the PrV UL11 protein, like glycoproteins E, I, and M, appears to be involved in secondary envelopment.
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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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Bochman, Matthew L., Katrin Paeschke, and Virginia A. Zakian. "DNA secondary structures: stability and function of G-quadruplex structures." Nature Reviews Genetics 13, no. 11 (October 3, 2012): 770–80. http://dx.doi.org/10.1038/nrg3296.
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Mayer, Günter, Lenz Kröck, Vera Mikat, Marianne Engeser, and Alexander Heckel. "Light-Induced Formation of G-Quadruplex DNA Secondary Structures." ChemBioChem 6, no. 11 (September 22, 2005): 1966–70. http://dx.doi.org/10.1002/cbic.200500198.
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Asamitsu, Sefan, Masayuki Takeuchi, Susumu Ikenoshita, Yoshiki Imai, Hirohito Kashiwagi, and Norifumi Shioda. "Perspectives for Applying G-Quadruplex Structures in Neurobiology and Neuropharmacology." International Journal of Molecular Sciences 20, no. 12 (June 13, 2019): 2884. http://dx.doi.org/10.3390/ijms20122884.
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The most common form of DNA is a right-handed helix or the B-form DNA. DNA can also adopt a variety of alternative conformations, non-B-form DNA secondary structures, including the DNA G-quadruplex (DNA-G4). Furthermore, besides stem-loops that yield A-form double-stranded RNA, non-canonical RNA G-quadruplex (RNA-G4) secondary structures are also observed. Recent bioinformatics analysis of the whole-genome and transcriptome obtained using G-quadruplex–specific antibodies and ligands, revealed genomic positions of G-quadruplexes. In addition, accumulating evidence pointed to the existence of these structures under physiologically- and pathologically-relevant conditions, with functional roles in vivo. In this review, we focused on DNA-G4 and RNA-G4, which may have important roles in neuronal function, and reveal mechanisms underlying neurological disorders related to synaptic dysfunction. In addition, we mention the potential of G-quadruplexes as therapeutic targets for neurological diseases.
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Miglietta, Giulia, Marco Russo, and Giovanni Capranico. "G-quadruplex–R-loop interactions and the mechanism of anticancer G-quadruplex binders." Nucleic Acids Research 48, no. 21 (November 2, 2020): 11942–57. http://dx.doi.org/10.1093/nar/gkaa944.
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Abstract Genomic DNA and cellular RNAs can form a variety of non-B secondary structures, including G-quadruplex (G4) and R-loops. G4s are constituted by stacked guanine tetrads held together by Hoogsteen hydrogen bonds and can form at key regulatory sites of eukaryote genomes and transcripts, including gene promoters, untranslated exon regions and telomeres. R-loops are 3-stranded structures wherein the two strands of a DNA duplex are melted and one of them is annealed to an RNA. Specific G4 binders are intensively investigated to discover new effective anticancer drugs based on a common rationale, i.e.: the selective inhibition of oncogene expression or specific impairment of telomere maintenance. However, despite the high number of known G4 binders, such a selective molecular activity has not been fully established and several published data point to a different mode of action. We will review published data that address the close structural interplay between G4s and R-loops in vitro and in vivo, and how these interactions can have functional consequences in relation to G4 binder activity. We propose that R-loops can play a previously-underestimated role in G4 binder action, in relation to DNA damage induction, telomere maintenance, genome and epigenome instability and alterations of gene expression programs.
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Sanchez-Martin, Victoria, Carmen Lopez-Pujante, Miguel Soriano-Rodriguez, and Jose A. Garcia-Salcedo. "An Updated Focus on Quadruplex Structures as Potential Therapeutic Targets in Cancer." International Journal of Molecular Sciences 21, no. 23 (November 24, 2020): 8900. http://dx.doi.org/10.3390/ijms21238900.
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Non-canonical, four-stranded nucleic acids secondary structures are present within regulatory regions in the human genome and transcriptome. To date, these quadruplex structures include both DNA and RNA G-quadruplexes, formed in guanine-rich sequences, and i-Motifs, found in cytosine-rich sequences, as their counterparts. Quadruplexes have been extensively associated with cancer, playing an important role in telomere maintenance and control of genetic expression of several oncogenes and tumor suppressors. Therefore, quadruplex structures are considered attractive molecular targets for cancer therapeutics with novel mechanisms of action. In this review, we provide a general overview about recent research on the implications of quadruplex structures in cancer, firstly gathering together DNA G-quadruplexes, RNA G-quadruplexes as well as DNA i-Motifs.
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Dey, Surjendu, and Andres Jäschke. "Covalently Functionalized DNA Duplexes and Quadruplexes as Hybrid Catalysts in an Enantioselective Friedel–Crafts Reaction." Molecules 25, no. 14 (July 8, 2020): 3121. http://dx.doi.org/10.3390/molecules25143121.
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The precise site-specific positioning of metal–ligand complexes on various DNA structures through covalent linkages has gained importance in the development of hybrid catalysts for aqueous-phase homogeneous catalysis. Covalently modified double-stranded and G-quadruplex DNA-based hybrid catalysts have been investigated separately. To understand the role of different DNA secondary structures in enantioselective Friedel–Crafts alkylation, a well-known G-quadruplex-forming sequence was covalently modified at different positions. The catalytic performance of this modified DNA strand was studied in the presence and absence of a complementary DNA sequence, resulting in the formation of two different secondary structures, namely duplex and G-quadruplex. Indeed, the secondary structures had a tremendous effect on both the yield and stereoselectivity of the catalyzed reaction. In addition, the position of the modification, the topology of the DNA, the nature of the ligand, and the length of the linker between ligand and DNA were found to modulate the catalytic performance of the hybrid catalysts. Using the optimal linker length, the quadruplexes formed the (−)-enantiomer with up to 65% ee, while the duplex yielded the (+)-enantiomer with up to 62% ee. This study unveils a new and simple way to control the stereochemical outcome of a Friedel–Crafts reaction.
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Raguseo, Federica, Souroprobho Chowdhury, Aisling Minard, and Marco Di Antonio. "Chemical-biology approaches to probe DNA and RNA G-quadruplex structures in the genome." Chemical Communications 56, no. 9 (2020): 1317–24. http://dx.doi.org/10.1039/c9cc09107f.
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G-quadruplexes are nucleic-acids secondary structures that can be formed under physiological conditions. In this review, we critically present the most relevant chemical-biology methods to probe the biological functions of G-quadruplex structures.
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David, Aldana P., Angélique Pipier, Federico Pascutti, Andrés Binolfi, Andrea M. J. Weiner, Emilse Challier, Sofía Heckel, et al. "CNBP controls transcription by unfolding DNA G-quadruplex structures." Nucleic Acids Research 47, no. 15 (June 20, 2019): 7901–13. http://dx.doi.org/10.1093/nar/gkz527.
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Abstract Guanine-rich DNA strands can fold into non-canonical four-stranded secondary structures named G-quadruplexes (G4). Experimental evidences suggest that G4-DNA surrounding transcription start sites act as cis-regulatory elements by either stimulating or inhibiting gene transcription. Therefore, proteins able to target and regulate specific G4 formation/unfolding are crucial for G4-mediated transcriptional control. Here we present data revealing that CNBP acts in vitro as a G4-unfolding protein over a tetramolecular G4 formed by the TG4T oligonucleotide, as well as over the G4 folded in the promoters of several oncogenes. CNBP depletion in cellulo led to a reduction in the transcription of endogenous KRAS, suggesting a regulatory role of CNBP in relieving the transcriptional abrogation due to G4 formation. CNBP activity was also assayed over the evolutionary conserved G4 enhancing the transcription of NOGGIN (NOG) developmental gene. CNBP unfolded in vitro NOG G4 and experiments performed in cellulo and in vivo in developing zebrafish showed a repressive role of CNBP on the transcription of this gene by G4 unwinding. Our results shed light on the mechanisms underlying CNBP way of action, as well as reinforce the notion about the existence and function of G4s in whole living organisms.
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Sanchez-Martin, Victoria. "DNA G-Quadruplex-Binding Proteins: An Updated Overview." DNA 3, no. 1 (January 11, 2023): 1–12. http://dx.doi.org/10.3390/dna3010001.
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DNA G-quadruplexes (G4s) are non-canonical secondary structures formed in guanine-rich sequences. Within the human genome, G4s are found in regulatory regions such as gene promoters and telomeres to control replication, transcription, and telomere lengthening. In the cellular context, there are several proteins named as G4-binding proteins (G4BPs) that interact with G4s, either anchoring upon, stabilizing, and/or unwinding them. These proteins may play different key roles in the regulation of the endogenous G4 landscape and its associated functions. The present review summarizes the current literature on G4BPs in terms of their targets and functions, providing updated insights into the regulation of G4s in living organisms.
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Criscuolo, Andrea, Ettore Napolitano, Claudia Riccardi, Domenica Musumeci, Chiara Platella, and Daniela Montesarchio. "Insights into the Small Molecule Targeting of Biologically Relevant G-Quadruplexes: An Overview of NMR and Crystal Structures." Pharmaceutics 14, no. 11 (November 1, 2022): 2361. http://dx.doi.org/10.3390/pharmaceutics14112361.
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G-quadruplexes turned out to be important targets for the development of novel targeted anticancer/antiviral therapies. More than 3000 G-quadruplex small-molecule ligands have been described, with most of them exerting anticancer/antiviral activity by inducing telomeric damage and/or altering oncogene or viral gene expression in cancer cells and viruses, respectively. For some ligands, in-depth NMR and/or crystallographic studies were performed, providing detailed knowledge on their interactions with diverse G-quadruplex targets. Here, the PDB-deposited NMR and crystal structures of the complexes between telomeric, oncogenic or viral G-quadruplexes and small-molecule ligands, of both organic and metal-organic nature, have been summarized and described based on the G-quadruplex target, from telomeric DNA and RNA G-quadruplexes to DNA oncogenic G-quadruplexes, and finally to RNA viral G-quadruplexes. An overview of the structural details of these complexes is here provided to guide the design of novel ligands targeting more efficiently and selectively cancer- and virus-related G-quadruplex structures.
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Robinson, Jenna, Federica Raguseo, Sabrina Pia Nuccio, Denise Liano, and Marco Di Antonio. "DNA G-quadruplex structures: more than simple roadblocks to transcription?" Nucleic Acids Research 49, no. 15 (July 13, 2021): 8419–31. http://dx.doi.org/10.1093/nar/gkab609.
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Abstract It has been >20 years since the formation of G-quadruplex (G4) secondary structures in gene promoters was first linked to the regulation of gene expression. Since then, the development of small molecules to selectively target G4s and their cellular application have contributed to an improved understanding of how G4s regulate transcription. One model that arose from this work placed these non-canonical DNA structures as repressors of transcription by preventing polymerase processivity. Although a considerable number of studies have recently provided sufficient evidence to reconsider this simplistic model, there is still a misrepresentation of G4s as transcriptional roadblocks. In this review, we will challenge this model depicting G4s as simple ‘off switches’ for gene expression by articulating how their formation has the potential to alter gene expression at many different levels, acting as a key regulatory element perturbing the nature of epigenetic marks and chromatin architecture.
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Minard, Aisling, Danielle Morgan, Federica Raguseo, Anna Di Porzio, Denise Liano, Andrew G. Jamieson, and Marco Di Antonio. "A short peptide that preferentially binds c-MYC G-quadruplex DNA." Chemical Communications 56, no. 63 (2020): 8940–43. http://dx.doi.org/10.1039/d0cc02954h.
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G-quadruplexes are nucleic-acids secondary structures that are highly abundant in the human genome. In this work,we identified a short-peptide that displays selectivity for the G-quadruplex formed in the promoter region of the oncogene c-MYC.
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Götz, Silvia, Satyaprakash Pandey, Sabrina Bartsch, Stefan Juranek, and Katrin Paeschke. "A Novel G-Quadruplex Binding Protein in Yeast—Slx9." Molecules 24, no. 9 (May 7, 2019): 1774. http://dx.doi.org/10.3390/molecules24091774.
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G-quadruplex (G4) structures are highly stable four-stranded DNA and RNA secondary structures held together by non-canonical guanine base pairs. G4 sequence motifs are enriched at specific sites in eukaryotic genomes, suggesting regulatory functions of G4 structures during different biological processes. Considering the high thermodynamic stability of G4 structures, various proteins are necessary for G4 structure formation and unwinding. In a yeast one-hybrid screen, we identified Slx9 as a novel G4-binding protein. We confirmed that Slx9 binds to G4 DNA structures in vitro. Despite these findings, Slx9 binds only insignificantly to G-rich/G4 regions in Saccharomyces cerevisiae as demonstrated by genome-wide ChIP-seq analysis. However, Slx9 binding to G4s is significantly increased in the absence of Sgs1, a RecQ helicase that regulates G4 structures. Different genetic and molecular analyses allowed us to propose a model in which Slx9 recognizes and protects stabilized G4 structures in vivo.
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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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Stroik, Susanna, Kevin Kurtz, Kevin Lin, Sergey Karachenets, Chad L. Myers, Anja-Katrin Bielinsky, and Eric A. Hendrickson. "EXO1 resection at G-quadruplex structures facilitates resolution and replication." Nucleic Acids Research 48, no. 9 (March 31, 2020): 4960–75. http://dx.doi.org/10.1093/nar/gkaa199.
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Abstract G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.
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Kendrick, Samantha, and Laurence H. Hurley. "The role of G-quadruplex/i-motif secondary structures as cis-acting regulatory elements." Pure and Applied Chemistry 82, no. 8 (June 4, 2010): 1609–21. http://dx.doi.org/10.1351/pac-con-09-09-29.
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The nature of DNA has captivated scientists for more than 50 years. The discovery of the double-helix model of DNA by Watson and Crick in 1953 not only established the primary structure of DNA, but also provided the mechanism behind DNA function. Since then, researchers have continued to further the understanding of DNA structure and its pivotal role in transcription. The demonstration of DNA secondary structure formation has allowed for the proposal that the dynamics of DNA itself can function to modulate transcription. This review presents evidence that DNA can exist in a dynamic equilibrium between duplex and secondary conformations. In addition, data demonstrating that intracellular proteins as well as small molecules can shift this equilibrium in either direction to alter gene transcription will be discussed, with a focus on the modulation of proto-oncogene expression.
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Scheibye-Knudsen, Morten, Anne Tseng, Martin Borch Jensen, Karsten Scheibye-Alsing, Evandro Fei Fang, Teruaki Iyama, Sanjay Kumar Bharti, et al. "Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA." Proceedings of the National Academy of Sciences 113, no. 44 (October 18, 2016): 12502–7. http://dx.doi.org/10.1073/pnas.1610198113.
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Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.
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Sanchez-Martin, Victoria, Miguel Soriano, and Jose Antonio Garcia-Salcedo. "Quadruplex Ligands in Cancer Therapy." Cancers 13, no. 13 (June 24, 2021): 3156. http://dx.doi.org/10.3390/cancers13133156.
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Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.
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Norseen, Julie, F. Brad Johnson, and Paul M. Lieberman. "Role for G-Quadruplex RNA Binding by Epstein-Barr Virus Nuclear Antigen 1 in DNA Replication and Metaphase Chromosome Attachment." Journal of Virology 83, no. 20 (August 5, 2009): 10336–46. http://dx.doi.org/10.1128/jvi.00747-09.
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ABSTRACT Latent infection by Epstein-Barr virus (EBV) requires both replication and maintenance of the viral genome. EBV nuclear antigen 1 (EBNA1) is a virus-encoded protein that is critical for the replication and maintenance of the genome during latency in proliferating cells. We have previously demonstrated that EBNA1 recruits the cellular origin recognition complex (ORC) through an RNA-dependent interaction with EBNA1 linking region 1 (LR1) and LR2. We now show that LR1 and LR2 bind to G-rich RNA that is predicted to form G-quadruplex structures. Several chemically distinct G-quadruplex-interacting drugs disrupted the interaction between EBNA1 and ORC. The G-quadruplex-interacting compound BRACO-19 inhibited EBNA1-dependent stimulation of viral DNA replication and preferentially blocked proliferation of EBV-positive cells relative to EBV-negative cell lines. BRACO-19 treatment also disrupted the ability of EBNA1 to tether to metaphase chromosomes, suggesting that maintenance function is also mediated through G-quadruplex recognition. These findings suggest that the EBNA1 replication and maintenance function uses a common G-quadruplex binding capacity of LR1 and LR2, which may be targetable by small-molecule inhibitors.
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Hurley, L. H. "Secondary DNA structures as molecular targets for cancer therapeutics." Biochemical Society Transactions 29, no. 6 (November 1, 2001): 692–96. http://dx.doi.org/10.1042/bst0290692.
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DNA sequence information is pivotal to transcription, replication and recombination. DNA structure is dependent upon intracellular conditions such as ion concentration and the presence of proteins that may bind to DNA to facilitate the interconversion between different forms and to stabilize specific secondary structures. Dependent upon the primary DNA sequence, purine- and pyrimidine-rich strands of DNA can adopt four-stranded structures known as G-quadruplexes and i-motifs, respectively. These structures have been proposed to exist in biologically important regions of DNA, e.g. at the end of chromosomes and in the regulatory regions of oncogenes such as c-myc. Proteins such as topoisomerase I and Rap1 can facilitate the formation of G-quadruplex structures, and for transcriptional activation of c-myc, proteins such as NM23–H2 and hnRNP K are required. These proteins bind to the non-duplex forms of the nuclease hypersensitivity element III, of c-myc. The design and synthesis of small molecules that target these secondary DNA structures and the biochemical and biological effects of these compounds are of potential importance in cancer chemotherapy.
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Neupane, Aryan, Julia H. Chariker, and Eric C. Rouchka. "Structural and Functional Classification of G-Quadruplex Families within the Human Genome." Genes 14, no. 3 (March 4, 2023): 645. http://dx.doi.org/10.3390/genes14030645.
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G-quadruplexes (G4s) are short secondary DNA structures located throughout genomic DNA and transcribed RNA. Although G4 structures have been shown to form in vivo, no current search tools that examine these structures based on previously identified G-quadruplexes and filter them based on similar sequence, structure, and thermodynamic properties are known to exist. We present a framework for clustering G-quadruplex sequences into families using the CD-HIT, MeShClust, and DNACLUST methods along with a combination of Starcode and BLAST. Utilizing this framework to filter and annotate clusters, 95 families of G-quadruplex sequences were identified within the human genome. Profiles for each family were created using hidden Markov models to allow for the identification of additional family members and generate homology probability scores. The thermodynamic folding energy properties, functional annotation of genes associated with the sequences, scores from different prediction algorithms, and transcription factor binding motifs within a family were used to annotate and compare the diversity within and across clusters. The resulting set of G-quadruplex families can be used to further understand how different regions of the genome are regulated by factors targeting specific structures common to members of a specific cluster.
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Xiao, Chao-Da, Zhi-Yong He, Chuan-Xin Guo, Xiang-Chun Shen, and Yan Xu. "Conformation of G-quadruplex Controlled by Click Reaction." Molecules 25, no. 18 (September 22, 2020): 4339. http://dx.doi.org/10.3390/molecules25184339.
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G-quadruplexes are non-canonical four stranded secondary structures possessing great biological importance. Controlling G-quadruplex conformation for further regulating biological processes is both exciting and challenging. In this study, we described a method for regulating G-quadruplex conformation by click chemistry for the first time. 8-ethynyl-2′-deoxyguanosine was synthesized and incorporated into a 12-nt telomere DNA sequence. Such a sequence, at first, formed mixed parallel/anti-parallel G-quadruplexes, while it changed to anti-parallel after reaction with azidobenzene. Meanwhile, the click reaction can give the sequence intense fluorescence.
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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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Galati, Elena, Maria C. Bosio, Daniele Novarina, Matteo Chiara, Giulia M. Bernini, Alessandro M. Mozzarelli, Maria L. García-Rubio, et al. "VID22 counteracts G-quadruplex-induced genome instability." Nucleic Acids Research 49, no. 22 (December 6, 2021): 12785–804. http://dx.doi.org/10.1093/nar/gkab1156.
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Abstract Genome instability is a condition characterized by the accumulation of genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways affecting endogenous DNA damage and genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, reported to be involved in DNA double-strand break repair. vid22Δ cells exhibit increased levels of endogenous DNA damage, chronic DNA damage response activation and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. Vid22 binds to and protects DNA at G4-containing regions both in vitro and in vivo. Loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. Moreover, the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism.
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Mayer, Günter, Lenz Kröck, Vera Mikat, Marianne Engeser, and Alexander Heckel. "Cover Picture: Light-Induced Formation of G-Quadruplex DNA Secondary Structures (ChemBioChem 11/2005)." ChemBioChem 6, no. 11 (October 26, 2005): 1913. http://dx.doi.org/10.1002/cbic.200590036.
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Zenkov, Roman G., Kirill I. Kirsanov, Anna M. Ogloblina, Olga A. Vlasova, Denis S. Naberezhnov, Natalia Y. Karpechenko, Timur I. Fetisov, et al. "Effects of G-Quadruplex-Binding Plant Secondary Metabolites on c-MYC Expression." International Journal of Molecular Sciences 23, no. 16 (August 16, 2022): 9209. http://dx.doi.org/10.3390/ijms23169209.
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Guanine-rich DNA sequences tending to adopt noncanonical G-quadruplex (G4) structures are over-represented in promoter regions of oncogenes. Ligands recognizing G4 were shown to stabilize these DNA structures and drive their formation regulating expression of corresponding genes. We studied the interaction of several plant secondary metabolites (PSMs) with G4s and their effects on gene expression in a cellular context. The binding of PSMs with G4s formed by the sequences of well-studied oncogene promoters and telomeric repeats was evaluated using a fluorescent indicator displacement assay. c-MYC G4 folding topology and thermal stability, as well as the PMS influence on these parameters, were demonstrated by UV-spectroscopy and circular dichroism. The effects of promising PSMs on c-MYC expression were assessed using luciferase reporter assay and qPR-PCR in cancer and immortalized cultured cells. The ability of PMS to multi-targeting cell signaling pathways was analyzed by the pathway-focused gene expression profiling with qRT-PCR. The multi-target activity of a number of PSMs was demonstrated by their interaction with a set of G4s mimicking those formed in the human genome. We have shown a direct G4-mediated down regulation of c-MYC expression by sanguinarine, quercetin, kaempferol, and thymoquinone; these effects being modulated by PSM’s indirect influence via cell signaling pathways.
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Dickerhoff, Jonathan, Kassandra R. Warnecke, Kaibo Wang, Nanjie Deng, and Danzhou Yang. "Evaluating Molecular Docking Software for Small Molecule Binding to G-Quadruplex DNA." International Journal of Molecular Sciences 22, no. 19 (October 6, 2021): 10801. http://dx.doi.org/10.3390/ijms221910801.
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G-quadruplexes are four-stranded nucleic acid secondary structures of biological significance and have emerged as an attractive drug target. The G4 formed in the MYC promoter (MycG4) is one of the most studied small-molecule targets, and a model system for parallel structures that are prevalent in promoter DNA G4s and RNA G4s. Molecular docking has become an essential tool in structure-based drug discovery for protein targets, and is also increasingly applied to G4 DNA. However, DNA, and in particular G4, binding sites differ significantly from protein targets. Here we perform the first systematic evaluation of four commonly used docking programs (AutoDock Vina, DOCK 6, Glide, and RxDock) for G4 DNA-ligand binding pose prediction using four small molecules whose complex structures with the MycG4 have been experimentally determined in solution. The results indicate that there are considerable differences in the performance of the docking programs and that DOCK 6 with GB/SA rescoring performs better than the other programs. We found that docking accuracy is mainly limited by the scoring functions. The study shows that current docking programs should be used with caution to predict G4 DNA-small molecule binding modes.
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Falanga, Andrea P., Monica Terracciano, Giorgia Oliviero, Giovanni N. Roviello, and Nicola Borbone. "Exploring the Relationship between G-Quadruplex Nucleic Acids and Plants: From Plant G-Quadruplex Function to Phytochemical G4 Ligands with Pharmaceutic Potential." Pharmaceutics 14, no. 11 (November 4, 2022): 2377. http://dx.doi.org/10.3390/pharmaceutics14112377.
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G-quadruplex (G4) oligonucleotides are higher-order DNA and RNA secondary structures of enormous relevance due to their implication in several biological processes and pathological states in different organisms. Strategies aiming at modulating human G4 structures and their interrelated functions are first-line approaches in modern research aiming at finding new potential anticancer treatments or G4-based aptamers for various biomedical and biotechnological applications. Plants offer a cornucopia of phytocompounds that, in many cases, are effective in binding and modulating the thermal stability of G4s and, on the other hand, contain almost unexplored G4 motifs in their genome that could inspire new biotechnological strategies. Herein, we describe some G4 structures found in plants, summarizing the existing knowledge of their functions and biological role. Moreover, we review some of the most promising G4 ligands isolated from vegetal sources and report on the known relationships between such phytochemicals and G4-mediated biological processes that make them potential leads in the pharmaceutical sector.
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Desai, Nakshi, Viraj Shah, and Bhaskar Datta. "Assessing G4-Binding Ligands In Vitro and in Cellulo Using Dimeric Carbocyanine Dye Displacement Assay." Molecules 26, no. 5 (March 5, 2021): 1400. http://dx.doi.org/10.3390/molecules26051400.
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G-quadruplexes (G4) are the most actively studied non-canonical secondary structures formed by contiguous repeats of guanines in DNA or RNA strands. Small molecule mediated targeting of G-quadruplexes has emerged as an attractive tool for visualization and stabilization of these structures inside the cell. Limited number of DNA and RNA G4-selective assays have been reported for primary ligand screening. A combination of fluorescence spectroscopy, AFM, CD, PAGE, and confocal microscopy have been used to assess a dimeric carbocyanine dye B6,5 for screening G4-binding ligands in vitro and in cellulo. The dye B6,5 interacts with physiologically relevant DNA and RNA G4 structures, resulting in fluorescence enhancement of the molecule as an in vitro readout for G4 selectivity. Interaction of the dye with G4 is accompanied by quadruplex stabilization that extends its use in primary screening of G4 specific ligands. The molecule is cell permeable and enables visualization of quadruplex dominated cellular regions of nucleoli using confocal microscopy. The dye is displaced by quarfloxin in live cells. The dye B6,5 shows remarkable duplex to quadruplex selectivity in vitro along with ligand-like stabilization of DNA G4 structures. Cell permeability and response to RNA G4 structures project the dye with interesting theranostic potential. Our results validate that B6,5 can serve the dual purpose of visualization of DNA and RNA G4 structures and screening of G4 specific ligands, and adds to the limited number of probes with such potential.
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Krafčíková, Petra, Erika Demkovičová, Andrea Halaganová, and Viktor Víglaský. "Putative HIV and SIV G-Quadruplex Sequences in Coding and Noncoding Regions Can Form G-Quadruplexes." Journal of Nucleic Acids 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/6513720.
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The HIV virus is one of the most studied viruses in the world. This is especially true in terms of gene sequencing, and to date more than 9 thousand genomic sequences of HIV isolates have been sequenced and analyzed. In this study, a series of DNA sequences, which have the potential to form G-quadruplex structures, is analyzed. Several such sequences were found in various coding and noncoding virus domains, including the U3 LTR, tat, rev, env, and vpx regions. Interestingly, a homological sequence to the already well-known HIV integrase aptamer was identified in the minus-strand. The sequences derived from original isolates were analyzed using standard spectral and electrophoretic methods. In addition, a recently developed methodology is applied which uses induced circular dichroism spectral profiles of G-quadruplex-ligand (Thiazole Orange) complexes to determine if G-rich sequences can adopt G-quadruplex structure. Targeting the G-quadruplexes or peptide domains corresponding to the G-rich coding sequence in HIV offers researchers attractive therapeutic targets which would be of particular use in the development of novel antiviral therapies. The analysis of G-rich regions can provide researchers with a path to find specific targets which could be of interest for specific types of virus.
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Shitikov, E. A., D. A. Bespiatykh, I. N. Bodoev, and M. V. Zaychikova. "G-quadruplex structures in bacteria: functional properties and prospects for use as biotargets." Biomeditsinskaya Khimiya 68, no. 2 (2022): 93–103. http://dx.doi.org/10.18097/pbmc20226802093.
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G-quadruplexes (G4), non-canonical secondary DNA structures, are intensively investigated for a long time. In eukaryotic organisms they play an important role in the regulation of gene expression and DNA repair. G4 have also been found in the genomes of numerous bacteria and archaea, but their functional role has not yet been fully explored. Nevertheless, their participation in the formation of antigenic variability, pathogenicity, antibiotic resistance and survival in extreme conditions has been established. Currently, many tools have been developed to detect potential G4 sequences and confirm their formation ability. Since the controlled formation and resolution of the quadruplex are significant means for the regulation of genes critical for survival, a promising direction is the search for ligands — compounds that can have a stabilizing effect on the quadruplex structure and thereby alter gene expression. Currently, a number of ligands are already known, their use stops the growth of pathogenic microorganisms. G4 ligands are of interest as potential antibiotics, which are extremely relevant due to the wide spread of drug resistant pathogens.
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Dahan, Danielle, Ioannis Tsirkas, Daniel Dovrat, Melanie A. Sparks, Saurabh P. Singh, Roberto Galletto, and Amir Aharoni. "Pif1 is essential for efficient replisome progression through lagging strand G-quadruplex DNA secondary structures." Nucleic Acids Research 46, no. 22 (November 5, 2018): 11847–57. http://dx.doi.org/10.1093/nar/gky1065.
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Mazzini, Stefania, Salvatore Princiotto, Loana Musso, Daniele Passarella, Giovanni Luca Beretta, Paola Perego, and Sabrina Dallavalle. "Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core." Molecules 27, no. 9 (April 27, 2022): 2791. http://dx.doi.org/10.3390/molecules27092791.
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G-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative 1 was synthesized and found to share the structural features typical of G-quadruplex binders. Herein, structural modifications were conducted on this scaffold in order to assist the binding with a G-quadruplex, by introducing charged hydrophilic groups. The antiproliferative activity of the new analogues was evaluated on an IGROV-1 human ovarian cancer cell line, and the most active compound, compound 9, was analyzed with NMR spectrometry in order to investigate its binding mode with DNA. The results indicated that a weak, non-specific interaction was set with duplex nucleotides; on the other hand, titration in the presence of a G-quadruplex from human telomere d(TTAGGGT)4 showed a stable, although not strong, interaction at the 3′-end of the nucleotidic sequence, efficiently assisted by salt bridges between the quaternary nitrogen and the external phosphate groups. Overall, this work can be considered a platform for the development of a new class of potential G-quadruplex stabilizing molecules, confirming the crucial role of a planar system and the ability of charged nitrogen-containing groups to facilitate the binding to G-quadruplex grooves and loops.
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Bua, Gloria, Daniele Tedesco, Ilaria Conti, Alessandro Reggiani, Manuela Bartolini, and Giorgio Gallinella. "No G-Quadruplex Structures in the DNA of Parvovirus B19: Experimental Evidence versus Bioinformatic Predictions." Viruses 12, no. 9 (August 25, 2020): 935. http://dx.doi.org/10.3390/v12090935.
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Parvovirus B19 (B19V), an ssDNA virus in the family Parvoviridae, is a human pathogenic virus, responsible for a wide range of clinical manifestations, still in need of effective and specific antivirals. DNA structures, including G-quadruplex (G4), have been recognised as relevant functional features in viral genomes, and small-molecule ligands binding to these structures are promising antiviral compounds. Bioinformatic tools predict the presence of potential G4 forming sequences (PQSs) in the genome of B19V, raising interest as targets for antiviral strategies. Predictions locate PQSs in the genomic terminal regions, in proximity to replicative origins. The actual propensity of these PQSs to form G4 structures was investigated by circular dichroism spectroscopic analysis on synthetic oligonucleotides of corresponding sequences. No signature of G4 structures was detected, and the interaction with the G4 ligand BRACO-19 (N,N′-(9-{[4-(dimethylamino)phenyl]amino}acridine-3,6-diyl)bis(3-pyrrolidin-1-ylpropanamide) did not appear consistent with the stabilisation of G4 structures. Any potential role of PQSs in the viral lifecycle was then assessed in an in vitro infection model system, by evaluating any variation in replication or expression of B19V in the presence of the G4 ligands BRACO-19 and pyridostatin. Neither showed a significant inhibitory activity on B19V replication or expression. Experimental challenge did not support bioinformatic predictions. The terminal regions of B19V are characterised by relevant sequence and symmetry constraints, which are functional to viral replication. Our experiments suggest that these impose a stringent requirement prevailing over the propensity of forming actual G4 structures.
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Roychoudhury, Shrabasti, Suravi Pramanik, Hannah L. Harris, Mason Tarpley, Aniruddha Sarkar, Gaelle Spagnol, Paul L. Sorgen, et al. "Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome." Proceedings of the National Academy of Sciences 117, no. 21 (May 13, 2020): 11409–20. http://dx.doi.org/10.1073/pnas.1912355117.
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Formation of G-quadruplex (G4) DNA structures in key regulatory regions in the genome has emerged as a secondary structure-based epigenetic mechanism for regulating multiple biological processes including transcription, replication, and telomere maintenance. G4 formation (folding), stabilization, and unfolding must be regulated to coordinate G4-mediated biological functions; however, how cells regulate the spatiotemporal formation of G4 structures in the genome is largely unknown. Here, we demonstrate that endogenous oxidized guanine bases in G4 sequences and the subsequent activation of the base excision repair (BER) pathway drive the spatiotemporal formation of G4 structures in the genome. Genome-wide mapping of occurrence of Apurinic/apyrimidinic (AP) site damage, binding of BER proteins, and G4 structures revealed that oxidized base-derived AP site damage and binding of OGG1 and APE1 are predominant in G4 sequences. Loss of APE1 abrogated G4 structure formation in cells, which suggests an essential role of APE1 in regulating the formation of G4 structures in the genome. Binding of APE1 to G4 sequences promotes G4 folding, and acetylation of APE1, which enhances its residence time, stabilizes G4 structures in cells. APE1 subsequently facilitates transcription factor loading to the promoter, providing mechanistic insight into the role of APE1 in G4-mediated gene expression. Our study unravels a role of endogenous oxidized DNA bases and APE1 in controlling the formation of higher-order DNA secondary structures to regulate transcription beyond its well-established role in safeguarding the genomic integrity.
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Wu, Guanhui, Luying Chen, Kristen Huseman, Desiree Tillo, Sreejana Ray, Ta-Chau Chang, John S. Schneekloth, Charles Vinson, and Danzhou Yang. "Abstract 2756: Custom G4 DNA microarray can determine large-scale binding selectivity of small molecules and proteins to oncogene G-quadruplexes." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2756. http://dx.doi.org/10.1158/1538-7445.am2023-2756.
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Abstract G-quadruplexes are novel DNA secondary structures that are formed in guanine-rich genomic regions with functional importance in cancers, such as human telomeres and oncogene promoters. G-quadruplexes adopt globular structures distinct from duplex B-DNA and their structural diversity suggests specific recognition. G-quadruplexes have become attractive drug targets because they provide a means of addressing otherwise undruggable targets. As one example, MYC is an important oncogene that is difficult to target by traditional drug design; however, its regulation involves a promoter G-quadruplex (MycG4) that is a potential drug target. 3,6-bis(1-Methyl-4-vinylpyridinium) carbazole diiodide (BMVC) is the first fluorescent probe developed for detecting G-quadruplex structures in cells and has been tested for cancer cell diagnosis. Although it was designed to detect the G-quadruplexes formed in human telomeres, we found BMVC binds to the MYC promoter G-quadruplex (MycG4) with higher affinity and specificity. We determined the high-resolution NMR K+ solution structure of the 2:1 BMVC-MycG4 complex showing a novel conformational adjustment of BMVC for an optimal binding to G-quadruplexes. Intriguingly, BMVC binds the 5’-end of MycG4 with higher affinity, but it binds the 3’-end with greater sequence selectivity. To determine ligand-binding selectivity on a large-scale, we designed a new custom G-quadruplex microarray platform with more than 25,000 potential oncogene G4 sequences and mutants. The new microarray was able to systematically assess binding affinity and selectivity of drugs targeted to G4s like the G-quadruplex involved in MYC regulation. The microarray results show that BMVC preferentially binds to the parallel type of G-quadruplexes, especially MycG4. Importantly, a strong sequence selectivity of BMVC for a 3’ flanking T was observed, consistent with the NMR data. The new microarray was also able to systematically assess binding of proteins and antibodies in a high-throughput and unbiased manner, and we tested the G-quadruplex binding proteins FANCJ, PIF1, BLM, DHX36, WRN, IGF2, CNBP, nucleolin, as well as the G-quadruplex-specific antibody BG4. In conclusion, we establish the custom G4 DNA microarray which can be used to determine binding selectivity of small molecules and proteins to oncogene G-quadruplexes in large-scale and high-throughput. Citation Format: Guanhui Wu, Luying Chen, Kristen Huseman, Desiree Tillo, Sreejana Ray, Ta-Chau Chang, John S. Schneekloth, Charles Vinson, Danzhou Yang. Custom G4 DNA microarray can determine large-scale binding selectivity of small molecules and proteins to oncogene G-quadruplexes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2756.
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Lenarčič Živković, Martina, Jan Rozman, and Janez Plavec. "Structure of a DNA G-Quadruplex Related to Osteoporosis with a G-A Bulge Forming a Pseudo-loop." Molecules 25, no. 20 (October 21, 2020): 4867. http://dx.doi.org/10.3390/molecules25204867.
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Bone remodeling is a fine-tuned process principally regulated by a cascade triggered by interaction of receptor activator of NF-κB (RANK) and RANK ligand (RANKL). Excessive activity of the RANKL gene leads to increased bone resorption and can influence the incidence of osteoporosis. Although much has been learned about the intracellular signals activated by RANKL/RANK complex, significantly less is known about the molecular mechanisms of regulation of RANKL expression. Here, we report on the structure of an unprecedented DNA G-quadruplex, well-known secondary structure-mediated gene expression regulator, formed by a G-rich sequence found in the regulatory region of a RANKL gene. Solution-state NMR structural study reveals the formation of a three-layered parallel-type G-quadruplex characterized by an unique features, including a G-A bulge. Although a guanine within a G-tract occupies syn glycosidic conformation, bulge-forming residues arrange in a pseudo-loop conformation to facilitate partial 5/6-ring stacking, typical of G-quadruplex structures with parallel G-tracts orientation. Such distinctive structural features protruding from the core of the structure can represent a novel platform for design of highly specific ligands with anti-osteoporotic function. Additionally, our study suggests that the expression of RANKL gene may be regulated by putative folding of its G-rich region into non-B-DNA structure(s).
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Li, Conghui, Honghong Wang, Zhinang Yin, Pingping Fang, Ruijing Xiao, Ying Xiang, Wen Wang, et al. "Ligand-induced native G-quadruplex stabilization impairs transcription initiation." Genome Research 31, no. 9 (August 16, 2021): 1546–60. http://dx.doi.org/10.1101/gr.275431.121.
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G-quadruplexes (G4s) are noncanonical DNA secondary structures formed through the self-association of guanines, and G4s are distributed widely across the genome. G4 participates in multiple biological processes including gene transcription, and G4-targeted ligands serve as potential therapeutic agents for DNA-targeted therapies. However, genome-wide studies of the exact roles of G4s in transcriptional regulation are still lacking. Here, we establish a sensitive G4-CUT&Tag method for genome-wide profiling of native G4s with high resolution and specificity. We find that native G4 signals are cell type–specific and are associated with transcriptional regulatory elements carrying active epigenetic modifications. Drug-induced promoter-proximal RNA polymerase II pausing promotes nearby G4 formation. In contrast, G4 stabilization by G4-targeted ligands globally reduces RNA polymerase II occupancy at gene promoters as well as nascent RNA synthesis. Moreover, ligand-induced G4 stabilization modulates chromatin states and impedes transcription initiation via inhibition of general transcription factors loading to promoters. Together, our study reveals a reciprocal genome-wide regulation between native G4 dynamics and gene transcription, which will deepen our understanding of G4 biology toward therapeutically targeting G4s in human diseases.
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Cadoni, Enrico, Lessandro De Paepe, Alex Manicardi, and Annemieke Madder. "Beyond small molecules: targeting G-quadruplex structures with oligonucleotides and their analogues." Nucleic Acids Research 49, no. 12 (May 12, 2021): 6638–59. http://dx.doi.org/10.1093/nar/gkab334.
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Abstract G-Quadruplexes (G4s) are widely studied secondary DNA/RNA structures, naturally occurring when G-rich sequences are present. The strategic localization of G4s in genome areas of crucial importance, such as proto-oncogenes and telomeres, entails fundamental implications in terms of gene expression regulation and other important biological processes. Although thousands of small molecules capable to induce G4 stabilization have been reported over the past 20 years, approaches based on the hybridization of a synthetic probe, allowing sequence-specific G4-recognition and targeting are still rather limited. In this review, after introducing important general notions about G4s, we aim to list, explain and critically analyse in more detail the principal approaches available to target G4s by using oligonucleotides and synthetic analogues such as Locked Nucleic Acids (LNAs) and Peptide Nucleic Acids (PNAs), reporting on the most relevant examples described in literature to date.
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Shu, Huiling, Rongxin Zhang, Ke Xiao, Jing Yang, and Xiao Sun. "G-Quadruplex-Binding Proteins: Promising Targets for Drug Design." Biomolecules 12, no. 5 (April 29, 2022): 648. http://dx.doi.org/10.3390/biom12050648.
Full textAbstract:
G-quadruplexes (G4s) are non-canonical secondary nucleic acid structures. Sequences with the potential to form G4s are abundant in regulatory regions of the genome including telomeres, promoters and 5′ non-coding regions, indicating they fulfill important genome regulatory functions. Generally, G4s perform various biological functions by interacting with proteins. In recent years, an increasing number of G-quadruplex-binding proteins have been identified with biochemical experiments. G4-binding proteins are involved in vital cellular processes such as telomere maintenance, DNA replication, gene transcription, mRNA processing. Therefore, G4-binding proteins are also associated with various human diseases. An intensive study of G4-protein interactions provides an attractive approach for potential therapeutics and these proteins can be considered as drug targets for novel medical treatment. In this review, we present biological functions and structural properties of G4-binding proteins, and discuss how to exploit G4-protein interactions to develop new therapeutic targets.
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Wenzel, Jürgen J., Heidi Rossmann, Christian Fottner, Stefan Neuwirth, Carolin Neukirch, Peter Lohse, Julia K. Bickmann, et al. "Identification and Prevention of Genotyping Errors Caused by G-Quadruplex– and i-Motif–Like Sequences." Clinical Chemistry 55, no. 7 (July 1, 2009): 1361–71. http://dx.doi.org/10.1373/clinchem.2008.118661.
Full textAbstract:
Abstract Background: Reliable PCR amplification of DNA fragments is the prerequisite for most genetic assays. We investigated the impact of G-quadruplex– or i-motif–like sequences on the reliability of PCR-based genetic analyses. Methods: We found the sequence context of a common intronic polymorphism in the MEN1 gene (multiple endocrine neoplasia I) to be the cause of systematic genotyping errors by inducing preferential amplification of one allelic variant [allele dropout (ADO)]. Bioinformatic analyses and pyrosequencing-based allele quantification enabled the identification of the underlying DNA structures. Results: We showed that G-quadruplex– or i-motif–like sequences can reproducibly cause ADO. In these cases, amplification efficiency strongly depends on the PCR enzyme and buffer conditions, the magnesium concentration in particular. In a randomly chosen subset of candidate single-nucleotide polymorphisms (SNPs) defined by properties deduced from 2 originally identified ADO cases, we confirmed preferential PCR amplification in up to 50% of the SNPs. We subsequently identified G-quadruplex and i-motifs harboring a SNP that alters the typical motif as the cause of this phenomenon, and a genomewide search based on the respective motifs predicted 0.5% of all SNPs listed by dbSNP and Online Mendelian Inheritance in Man to be potentially affected. Conclusions: Undetected, the described phenomenon produces systematic errors in genetic analyses that may lead to misdiagnoses in clinical settings. PCR products should be checked for G-quadruplex and i-motifs to avoid the formation of ADO-causing secondary structures. Truly affected assays can then be identified by a simple experimental procedure, which simultaneously provides the solution to the problem. .
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Bryan, Tracy M. "G-Quadruplexes at Telomeres: Friend or Foe?" Molecules 25, no. 16 (August 13, 2020): 3686. http://dx.doi.org/10.3390/molecules25163686.
Full textAbstract:
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.