The Structure and Function of DNA G-Quadruplexes

Spiegel, Jochen; Adhikari, Santosh; Balasubramanian, Shankar

doi:10.1016/j.trechm.2019.07.002

Cited by 920DNA and Nucleic Acid ChemistryAdvanced biosensing and bioanalysis techniquesMetal complexes synthesis and properties

The Structure and Function of DNA G-Quadruplexes

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Spiegel, Jochen, Adhikari, Santosh, Balasubramanian, Shankar·2020·Trends in Chemistry

DOI 10.1016/j.trechm.2019.07.002PMC PMC7472594

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Abstract

Guanine-rich DNA sequences can fold into four-stranded, noncanonical secondary structures called G-quadruplexes (G4s). G4s were initially considered a structural curiosity, but recent evidence suggests their involvement in key genome functions such as transcription, replication, genome stability, and epigenetic regulation, together with numerous connections to cancer biology. Collectively, these advances have stimulated research probing G4 mechanisms and consequent opportunities for therapeutic intervention. Here, we provide a perspective on the structure and function of G4s with an emphasis on key molecules and methodological advances that enable the study of G4 structures in human cells. We also critically examine recent mechanistic insights into G4 biology and protein interaction partners and highlight opportunities for drug discovery.

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More serious DNA damages, such as double-strand breaks associated with non-B DNA structures like G4s, and the subsequent DNA repair can be mutagenic.
“Lastly, more serious DNA damages, such as double-strand breaks associated with non-B DNA structures like G4s, and the subsequent DNA repair can be mutagenic (7,27).”
From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [7]
The G4 Detection and Mapping section reports double-strand breaks predominantly at predicted G4 regions after treatment with a G4-stabilising ligand. The Intervention and Therapeutics section says G4 ligands cause double-strand breaks and activate DNA repair pathways, but does not say that the subsequent repair is mutagenic. The break evidence is also specifically tied to ligand treatment, a condition the claim omits. (LLM, conf=0.86)
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BackgroundInfluential
G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma
Wang, Y., Yang, J., Wild, A. T., Wu, W. H., Shah, R., Danussi, C., Riggins, G. J., Kannan, K., Sulman, E. P., Chan, T. A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08905-8 · Cited by 184 · cited 2× · see citing works
“Genomic binding sites of the chromatin remodelling protein ATR-X are enriched at GC-rich tandem repeats and CpG islands with the potential to fold G4 structures, and ATR-X loss is implicated with G4-dependent replication stress, DNA damage, and copy number alterations [53,82].”
Background
Structure-Based Design and Evaluation of Naphthalene Diimide G-Quadruplex Ligands As Telomere Targeting Agents in Pancreatic Cancer Cells
Micco, M., Collie, G. W., Dale, A. G., Ohnmacht, S. A., Pazitna, I., Gunaratnam, M., Reszka, A. P., & Neidle, S. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301899y · Cited by 184 · see citing works
G-quadruplex unwinding helicases and their function <i>in vivo</i>
Sauer, M., & Paeschke, K. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170097 · Cited by 179 · see citing works
Human replication protein A unfolds telomeric G-quadruplexes
Salas, T. R., Petruseva, I. O., Lavrik, O. I., Bourdoncle, A., Mergny, J., Favre, A., & Saintomé, C. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl564 · Cited by 177 · cited 1× · see citing works
“For instance, POT1 [75] and RPA [76], two components of the shelterin complex, as well as the human CST complex [77], are able to bind and unwind telomeric G4 structures and assist the action of telomerase.”
Background
Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression
Thakur, R. K., Kumar, P., Halder, K., Verma, A., Kar, A., Parent, J., Basundra, R., Kumar, A., & Chowdhury, S. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn919 · Cited by 174 · cited 1× · see citing works
“recognise and unwind the MYC promoter G4 [78].”
Background
G-Quadruplex DNA as a Molecular Target for Induced Synthetic Lethality in Cancer Cells
McLuckie, K. I. E., Antonio, M. D., Zecchini, H. I., Xian, J., Caldas, C., Krippendorff, B., Tannahill, D., Lowe, C., & Balasubramanian, S. (2013) · Journal of the American Chemical Society · doi:10.1021/ja404868t · Cited by 172 · cited 5× · see citing works
“G4 ligands such as pyridostatin and RHPS4 cause DNA double-strand breaks in cancer cells and activate DNA repair pathways [47,117].”
BackgroundInfluentialSelf-citation
G4LDB: a database for discovering and studying G-quadruplex ligands
Li, Q., Xiang, J., Yang, Q., Sun, H., Guan, A., & Tang, Y. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1101 · Cited by 166 · cited 1× · see citing works
“org/) [32], with some examples of widely used ligands”
Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule
Marchetti, C., Zyner, K. G., Ohnmacht, S. A., Robson, M. P., Haider, S. M., Morton, J. P., Marsico, G., Vo, T. D., Laughlin, S., Ahmed, A. A., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01781 · Cited by 166 · cited 3× · see citing works
“perspective, it is noteworthy that a G4 ligand that lacks traditional ‘drug-like’ properties has shown significant accumulation and efficacy in tumour xenografts of human cancers [29].”
BackgroundInfluentialSelf-citation
The dynamic response of upstream DNA to transcription-generated torsional stress
Kouzine, F., Liu, J.-H., Sanford, S., Chung, H.-J., & Levens, D. (2004) · Nature Structural &Molecular Biology · doi:10.1038/nsmb848 · Cited by 165 · cited 1× · see citing works
“upstream to mechanically perturb DNA structure [115] and it was suggested that a G4 and an i-motif can each be bound and stabilised by different specialised proteins to play opposite roles in the control of MYC gene transcription [116].”
Background
Structural polymorphism within a regulatory element of the human KRAS promoter: formation of G4-DNA recognized by nuclear proteins
Cogoi, S., Paramasivam, M., Spolaore, B., & Xodo, L. (2008) · Nucleic Acids Research · doi:10.1093/nar/gkn120 · Cited by 158 · see citing works
Replication of G Quadruplex DNA
Lerner, L. K., & Sale, J. E. (2019) · Genes · doi:10.3390/genes10020095 · Cited by 156 · cited 1× · see citing works
“Various models have been postulated for the biological role of G4 structures during DNA replication [100,101].”
Background
Machine learning model for sequence-driven DNA G-quadruplex formation
Sahakyan, A. B., Chambers, V. S., Marsico, G., Santner, T., di Antonio, M., & Balasubramanian, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-14017-4 · Cited by 154 · cited 1× · see citing works
“availability of large datasets on G4 formation has enabled the application of machine learning to predict G4 forming propensity [19].”
BackgroundSelf-citation
Altered gene expression in the Werner and Bloom syndromes is associated with sequences having G-quadruplex forming potential
Johnson, J. E., Cao, K.-J., Ryvkin, P., Wang, L.-S., & Johnson, F. B. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp1103 · Cited by 154 · cited 1× · see citing works
“in their promoter region, corroborating a link between G4s and transcription [107,108].”
Background
G-Quadruplexes in DNA Replication: A Problem or a Necessity?
Valton, A.-L., & Prioleau, M.-N. (2016) · Trends in Genetics · doi:10.1016/j.tig.2016.09.004 · Cited by 149 · cited 1× · see citing works
“Various models have been postulated for the biological role of G4 structures during DNA replication [100,101].”
Background
Click chemistry enables preclinical evaluation of targeted epigenetic therapies
Tyler, D. S., Vappiani, J., Cañeque, T., Lam, E. Y. N., Ward, A., Gilan, O., Chan, Y.-C., Hienzsch, A., Rutkowska, A., Werner, T., et al. (2017) · Science · doi:10.1126/science.aal2066 · Cited by 146 · cited 1× · see citing works
“The central hypothesis would be strengthened bymore explicit evidence for G4 ligands actually engaging with G4 structures in the promoters of affected genes in cells, for instance, by employing methods that enable the genome-wide mapping of ligand binding sites in native chromatin [30,31].”
Background
Protein hnRNP A1 and its derivative Up1 unfold quadruplex DNA in the human KRAS promoter: implications for transcription
Paramasivam, M., Membrino, A., Cogoi, S., Fukuda, H., Nakagama, H., & Xodo, L. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp138 · Cited by 144 · cited 1× · see citing works
“and HRAS promoter G4 in vitro, respectively [80,81].”
Background
A Role for the Fifth G-Track in G-Quadruplex Forming Oncogene Promoter Sequences during Oxidative Stress: Do These “Spare Tires” Have an Evolved Function?
Fleming, A., Zhou, J., Wallace, S., & Burrows, C. (2015) · ACS Central Science · doi:10.1021/acscentsci.5b00202 · Cited by 143 · see citing works
Telomerase recruitment by the telomere end binding protein-β facilitates G-quadruplex DNA unfolding in ciliates
Paeschke, K., Juranek, S., Simonsson, T., Hempel, A., Rhodes, D., & Lipps, H. J. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1422 · Cited by 141 · cited 1× · see citing works
“telomeric G4 structure formation was observed to be dynamically controlled through protein interactions in a cell cycle-dependent manner [39,40].”
Background
A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes
Papachristou, E., Kishore, K., Holding, A. N., Harvey, K., Roumeliotis, T. I., Chilamakuri, C., Omarjee, S., Chia, K., Swarbrick, A., Lim, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04619-5 · Cited by 138 · cited 1× · see citing works
“Approaches that can reveal the composition and dynamics of chromatin-associated protein complexes [87,88] will be needed to uncover details of the proteins that”
Background
The KRAS Promoter Responds to Myc-associated Zinc Finger and Poly(ADP-ribose) Polymerase 1 Proteins, Which Recognize a Critical Quadruplex-forming GA-element*
Cogoi, S., Paramasivam, M., Membrino, A., Yokoyama, K., & Xodo, L. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.101923 · Cited by 137 · cited 1× · see citing works
“Similarly, pull-down and chromatin immunoprecipitation experiments showed that Myc-associated zinc finger (MAZ) and poly(ADP-ribose) polymerase 1 (PARP-1) proteins bind the G4 structure found upstream of the KRAS transcription start site [79].”
Background
The regulatory G4 motif of the Kirsten ras (KRAS) gene is sensitive to guanine oxidation: implications on transcription
Cogoi, S., Ferino, A., Miglietta, G., Pedersen, E. B., & Xodo, L. E. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx1142 · Cited by 137 · see citing works
Rif1 binds to G quadruplexes and suppresses replication over long distances
Kanoh, Y., Matsumoto, S., Fukatsu, R., Kakusho, N., Kono, N., Renard-Guillet, C., Masuda, K., Iida, K., Nagasawa, K., Shirahige, K., et al. (2015) · Nature Structural &Molecular Biology · doi:10.1038/nsmb.3102 · Cited by 135 · cited 1×
“for a-thalassemia mental retardation X-linked (ATR-X) [53] and for the XPB and XPD helicases [54], yeast telomere binding protein RAP1-interacting factor 1 (Rif) [55], and yeast PIF1 helicase [56].”
Background
Crystal structure of a c-kit promoter quadruplex reveals the structural role of metal ions and water molecules in maintaining loop conformation
Wei, D., Parkinson, G., Reszka, A., & Neidle, S. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks023 · Cited by 134 · cited 1× · see citing works
“Structural studies using X-ray crystallography and NMR spectroscopy have provided detailed insights into the structure of DNA G4s primarily based on the human telomeric repeat (Figure 1B,C) [11] or sequences derived from the promoter regions of certain human genes such as MYC or KIT [12,13].”
Background
Conformation Selective Antibody Enables Genome Profiling and Leads to Discovery of Parallel G-Quadruplex in Human Telomeres
Liu, H., Zhao, Q., Zhang, T., Wu, Y., Xiong, Y., Wang, S., Ge, Y., He, J., Lv, P., Ou, T., et al. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2016.08.013 · Cited by 128 · cited 1× · see citing works
“G4 signals were found at transcription start sites, in introns and intergenic regions [44].”
Background
PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy
Salvati, E., Scarsella, M., Porru, M., Rizzo, A., Iachettini, S., Tentori, L., Graziani, G., D’Incalci, M., Stevens, M. F. G., Orlandi, A., et al. (2010) · Oncogene · doi:10.1038/onc.2010.344 · Cited by 123 · see citing works
Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs
Nguyen, G. H., Tang, W., Robles, A. I., Beyer, R. P., Graybuck, L. T., Welsh, J. A., Schetter, A. J., Kumamoto, K., Wang, X. W., Hickson, I. D., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1404807111 · Cited by 123 · cited 1× · see citing works
“in their promoter region, corroborating a link between G4s and transcription [107,108].”
Background
BLM helicase suppresses recombination at G-quadruplex motifs in transcribed genes
van Wietmarschen, N., Merzouk, S., Halsema, N., Spierings, D. C. J., Guryev, V., & Lansdorp, P. M. (2018) · Nature Communications · doi:10.1038/s41467-017-02760-1 · Cited by 118 · cited 1× · see citing works
“Moreover, BLM-mutated cells derived from Bloom syndrome patients show high rates of sister chromatid exchange at sites of G4 motifs in transcribed genes [109].”
Background
A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III1.
Sutherland, C., Cui, Y.-X., Mao, H., & Hurley, L. (2016) · Journal of the American Chemical Society · doi:10.1021/jacs.6b09196 · Cited by 114 · cited 1×
“upstream to mechanically perturb DNA structure [115] and it was suggested that a G4 and an i-motif can each be bound and stabilised by different specialised proteins to play opposite roles in the control of MYC gene transcription [116].”
Background
Identification of two human nuclear proteins that recognise the cytosine-rich strand of human telomeres in vitro
Lacroix, L. (2000) · Nucleic Acids Research · doi:10.1093/nar/28.7.1564 · Cited by 106 · see citing works
Mutually Exclusive Formation of G-Quadruplex and i-Motif Is a General Phenomenon Governed by Steric Hindrance in Duplex DNA.
Cui, Y.-X., Kong, D.-M., Ghimire, C., Xu, C.-X., & Mao, H. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00016 · Cited by 104 · cited 1×
“dencies or even be mutually exclusive [114].”
G4IPDB: A database for G-quadruplex structure forming nucleic acid interacting proteins
Mishra, S., Tawani, A., Mishra, A., & Kumar, A. (2016) · Scientific Reports · doi:10.1038/srep38144 · Cited by 102 · see citing works
Local epigenetic reprogramming induced by G-quadruplex ligands
Guilbaud, G., Murat, P., Recolin, B., Campbell, B. C., Maiter, A., Sale, J. E., & Balasubramanian, S. (2017) · Nature Chemistry · doi:10.1038/nchem.2828 · Cited by 101 · cited 1× · see citing works
“of G4 structures induced replication-dependent loss of epigenetic information showing that G4s can serve as obstacles to the replicationmachinery [104].”
BackgroundSelf-citation
HRAS is silenced by two neighboring G-quadruplexes and activated by MAZ, a zinc-finger transcription factor with DNA unfolding property
Cogoi, S., Shchekotikhin, A., & Xodo, L. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku574 · Cited by 100 · cited 1× · see citing works
“and HRAS promoter G4 in vitro, respectively [80,81].”
Background
Single-molecule imaging reveals a common mechanism shared by G-quadruplex–resolving helicases
Tippana, R., Hwang, H. J., Opresko, P. L., Bohr, V., & Myong, S. (2016) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1603724113 · Cited by 95
Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress
Byrd, A. K., Zybailov, B. L., Maddukuri, L., Gao, J., Marecki, J. C., Jaiswal, M., Bell, M. R., Griffin, W. C., Reed, M. R., Chib, S., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.718478 · Cited by 94 · see citing works
Dynamic DNA binding, junction recognition and G4 melting activity underlie the telomeric and genome-wide roles of human CST
Bhattacharjee, A., Wang, Y.-Y., Diao, J.-J., & Price, C. M. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx878 · Cited by 90 · cited 1× · see citing works
“For instance, POT1 [75] and RPA [76], two components of the shelterin complex, as well as the human CST complex [77], are able to bind and unwind telomeric G4 structures and assist the action of telomerase.”
Background
Confined space facilitates G-quadruplex formation
Shrestha, P., Jonchhe, S., Emura, T., Hidaka, K., Endo, M., Sugiyama, H., & Mao, H. (2017) · Nature Nanotechnology · doi:10.1038/nnano.2017.29 · Cited by 90 · cited 1× · see citing works
“Further considerations include the effects of molecular crowding [20] and DNA base modifications, such as cytosine methylation [21] and guanine oxida-”
Background
Identification of G-Quadruplex-Binding Protein from the Exploration of RGG Motif/G-Quadruplex Interactions.
Huang, Z.-L., Dai, J., Luo, W.-H., Wang, X., Tan, J.-H., Chen, S.-B., & Huang, Z.-S. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b09329 · Cited by 81 · cited 1×
“domains were compared to predict new putative G4 interactors [67,68].”
Background
Impact of Oxidative Lesions on the Human Telomeric G-Quadruplex
Bielskutė, S., Plavec, J., & Podbevšek, P. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.8b12748 · Cited by 80 · see citing works
Global profiling of protein–DNA and protein–nucleosome binding affinities using quantitative mass spectrometry
Makowski, M. M., Gräwe, C., Foster, B. M., Nguyen, N. V., Bartke, T., & Vermeulen, M. (2018) · Nature Communications · doi:10.1038/s41467-018-04084-0 · Cited by 78 · cited 1× · see citing works
“consensus sequences for hundreds of nuclear proteins in parallel [69].”
Background
Nucleotide Pool Depletion Induces G-Quadruplex-Dependent Perturbation of Gene Expression
Papadopoulou, C., Guilbaud, G., Schiavone, D., & Sale, J. E. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.11.039 · Cited by 71 · cited 1× · see citing works
“Additional replication stress due to nucleotide pool depletion decoupled the replication machinery from restoration of the parental histones, ultimately leading to altered gene expression [103].”
Background
Cytosine-cytosine+ base pairing stabilizes DNA quadruplexes and cytosine methylation greatly enhances the effect.
Hardin, C. C., Corregan, M., Brown, B. A., & Frederick, L. (1993) · Biochemistry · doi:10.1021/bi00073a021 · Cited by 70 · cited 1×
“Further considerations include the effects of molecular crowding [20] and DNA base modifications, such as cytosine methylation [21] and guanine oxida-”
Background
Molecular mechanisms by which oxidative DNA damage promotes telomerase activity
Lee, H.-T., Bose, A., Lee, C.-Y., Opresko, P. L., & Myong, S. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx789 · Cited by 69 · cited 1× · see citing works
“[98] and to promote telomerase activity [99].”
Tri-G-quadruplex: controlled assembly of a G-quadruplex structure from three G-rich strands.
Zhou, J., Bourdoncle, A., Rosu, F., Gabélica, V., & Mergny, J. (2012) · Angewandte Chemie · doi:10.1002/anie.201205390 · Cited by 65 · cited 1×
“ogies arising from different combinations of strand direction (Figure 1D–F), as well as length and loop composition [9,10].”
Background
The Amino Acid Composition of Quadruplex Binding Proteins Reveals a Shared Motif and Predicts New Potential Quadruplex Interactors
Brázda, V., Červeň, J., Bartas, M., Mikysková, N., Coufal, J., & Pečinka, P. (2018) · Molecules · doi:10.3390/molecules23092341 · Cited by 58 · see citing works
G-quadruplexes in promoters throughout the human genome
Huppert, J., & Balasubramanian, S. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm109 · Cited by 58 · cited 1×
“genome, of which a general enrichment was observed in regions associated with genome regulation, such as telomeres, promoters, and 50 untranslated regions [14,38].”
BackgroundSelf-citation
Copper–Alkyne Complexation Responsible for the Nucleolar Localization of Quadruplex Nucleic Acid Drugs Labeled by Click Reactions
Lefebvre, J., Guetta, C., Poyer, F., Mahuteau‐Betzer, F., & Teulade‐Fichou, M. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201703783 · Cited by 58 · see citing works
DNA G‐quadruplexes show strong interaction with DNA methyltransferases in vitro
Cree, S. L., Fredericks, R., Miller, A. L., Pearce, F. G., Filichev, V. V., Fee, C. J., & Kennedy, M. A. (2016) · FEBS Letters · doi:10.1002/1873-3468.12331 · Cited by 55 · cited 1× · see citing works
“The DNA methyltransferase enzymes (DNMTs), which catalyse the formation of 5-methylcytosine at CpG dinucleotides in mammalian cells, bind to G4 structures with subnanomolar affinity in vitro [83,84].”
Background
Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
Sengar, A., Vandana, J. J., Chambers, V. S., di Antonio, M., Winnerdy, F., Balasubramanian, S., & Phan, A. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1179 · Cited by 54 · cited 1×
“Subsequently, several G4 structures with longer loop lengths and discontinuities in G-stretches causing bulges were observed [16,17], leading to alternative predictive models [18].”
BackgroundSelf-citation
A guanine-flipping and sequestration mechanism for G-quadruplex unwinding by RecQ helicases
Voter, A. F., Qiu, Y., Tippana, R., Myong, S., & Keck, J. L. (2018) · Nature Communications · doi:10.1038/s41467-018-06751-8 · Cited by 52 · cited 1× · see citing works
“Werner (WRN) helicases, albeit with different substrate specificity, and showed the capacity to displace G4-stabilising ligands [71,72].”
Background
DNA damage processing at telomeres: The ends justify the means
Fouquerel, E., Parikh, D., & Opresko, P. L. (2016) · DNA repair · doi:10.1016/j.dnarep.2016.05.022 · Cited by 48 · cited 1× · see citing works
“The finding that G4-rich telomeric repeats form G4 structures [6] suggested a mechanistic link with telomerase-mediated extension of telomeres, prompting an exploration of G4 stabilising ligands that may inhibit the growth of cancer cells by interfering with telomere maintenance (reviewed in [89]).”
Background
CpG Methylation Changes G-Quadruplex Structures Derived from Gene Promoters and Interaction with VEGF and SP1
Tsukakoshi, K., Saito, S., Yoshida, W., Goto, S., & Ikebukuro, K. (2018) · Molecules · doi:10.3390/molecules23040944 · Cited by 46 · cited 1× · see citing works
“methylation can influence G4 topology [85] and may modulate binding by other G4-associated proteins.”
Background
Molecular Mechanistic Insights into Drosophila DHX36-Mediated G-Quadruplex Unfolding: A Structure-Based Model.
Chen, W.-F., Réty, S., Guo, H.-L., Dai, Y., Wu, W., Liu, N.-N., Auguin, D., Liu, Q.-W., Hou, X.-M., Dou, S.-X., et al. (2018) · Structure · doi:10.1016/j.str.2018.01.008 · Cited by 42
Expression of the human telomerase reverse transcriptase gene is modulated by quadruplex formation in its first exon due to DNA methylation
Li, P., Wang, Z., Chu, I.-T., Kuan, Y.-M., Li, M., Huang, M.-C., Chiang, P.-C., Chang, T., & Chen, C. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.808022 · Cited by 40 · see citing works
The Helicase PIF1 Facilitates Resection over Sequences Prone to Forming G4 Structures.
Jimeno, S., Camarillo, R., Mejías-Navarro, F., Fernández-Ávila, M. J., Soria-Bretones, I., Prados-Carvajal, R., & Huertas, P. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.12.029 · Cited by 39
Detection of G-quadruplex DNA in mammalian cells
Henderson, A., Wu, Y.-L., Huang, Y.-C., Chavez, E., Platt, J., Johnson, F., Brosh, R., Sen, D., & Lansdorp, P. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx300 · Cited by 31
Xanthine and 8-oxoguanine in G-quadruplexes: formation of a G·G·X·O tetrad
Cheong, V. V., Heddi, B., Lech, C., & Phan, A. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv826 · Cited by 31 · cited 1×
“tion [22], on the stability of G4 structures.”
Background

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4 of the 121 references couldn’t be matched to a known paper.

Research works printed but not linked: 3

[24]Testorelli C. Telomerase and cancer J. Exp. Clin. Cancer Res. 22 2003 165 169 12866565
[30]Anders L. Genome-wide localization of small molecules Nat. Biotechnol. 32 2014 92 96 24336317 PMC4189815
[63]Pagano B. Identification of novel interactors of human telomeric G-quadruplex DNA Chem. Commun. 51 2015 2964 2967 25594748

Sorted by citations

G-quadruplexes: a promising target for cancer therapy
Kosiol, N., Juranek, S., Brossart, P., Heine, A., & Paeschke, K. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01328-4 · Cited by 540 · see citing works
“The physiological relevance of G4 structures is further supported by the existence of proteins that are able to bind and unfold G4 structures [11, 12, 26].”
Background
Molecular Probes, Chemosensors, and Nanosensors for Optical Detection of Biorelevant Molecules and Ions in Aqueous Media and Biofluids
Krämer, J., Kang, R., Grimm, L., Cola, L. D., Picchetti, P., & Biedermann, F. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00746 · Cited by 455 · see citing works
DNA G-quadruplex structures: more than simple roadblocks to transcription?
Robinson, J., Raguseo, F., Nuccio, S. P., Liano, D., & Antonio, M. D. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab609 · Cited by 312 · see citing works
G-quadruplex, Friend or Foe: The Role of the G-quartet in Anticancer Strategies.
Carvalho, J., Mergny, J., Salgado, G., Queiroz, J., & Cruz, C. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.05.002 · Cited by 224 · see citing works
Alternative approaches to target Myc for cancer treatment
Wang, C., Zhang, J., Yin, J., Gan, Y., Xu, S., Gu, Y., & Huang, W. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00500-y · Cited by 243 · see citing works
“The quadruplex motifs are frequently over-represented in genes, which promote tumorigenesis.(21) Interestingly, the experimental data have shown that the Alternative approaches to target Myc for cancer treatment Wang et al.”
BackgroundInfluential
Molecular Crowding: The History and Development of a Scientific Paradigm
Alfano, C., Fichou, Y., Huber, K., Weiss, M., Spruijt, E., Ebbinghaus, S., Luca, G. D., Morando, M. A., Vetri, V., Temussi, P., et al. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.3c00615 · Cited by 177 · see citing works
Molecular photoswitches in aqueous environments
Volarić, J., Szymański, W., Simeth, N. A., & Feringa, B. L. (2021) · Chemical Society Reviews · doi:10.1039/d0cs00547a · Cited by 439 · see citing works
Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs
Seneff, S., Nigh, G., Kyriakopoulos, A. M., & McCullough, P. A. (2022) · Food and Chemical Toxicology · doi:10.1016/j.fct.2022.113008 · Cited by 177 · see citing works
Chemical profiling of DNA G-quadruplex-interacting proteins in live cells
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“1a) 14,15 .”
Self-citation
Properties and biological impact of RNA G-quadruplexes: from order to turmoil and back
Kharel, P., Becker, G., Цветков, В. Б., & Ivanov, P. V. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1126 · Cited by 163 · see citing works
“Subsequently, non-conventional G4s with longer loop lengths and discontinuities in G-stretches causing bulges were observed (11,12) leading to alternative predictive models (13,14).”
Background
G-quadruplex DNA: a novel target for drug design
Teng, F., Jiang, Z., Guo, M., Tan, X., Chen, F., Xi, X., & Xu, Y. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03921-8 · Cited by 136 · see citing works
G-quadruplex: Flexible conformational changes by cations, pH, crowding and its applications to biosensing
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DNA G-Quadruplex in Human Telomeres and Oncogene Promoters: Structures, Functions, and Small Molecule Targeting
Chen, L., Dickerhoff, J., Sakai, S., & Yang, D. (2022) · Accounts of Chemical Research · doi:10.1021/acs.accounts.2c00337 · Cited by 129
Recent progress in non-native nucleic acid modifications
McKenzie, L. K., El-Khoury, R., Thorpe, J. D., Damha, M. J., & Hollenstein, M. (2021) · Chemical Society Reviews · doi:10.1039/d0cs01430c · Cited by 300 · see citing works
G-quadruplex–R-loop interactions and the mechanism of anticancer G-quadruplex binders
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“G4 structures are heterogenous and many distinct conformations have been reported (1,2,11,84), however their roles in the mechanism of action of G4 binders is not known.”
Background
Static lung storage at 10°C maintains mitochondrial health and preserves donor organ function
Ali, A., Wang, A., Ribeiro, R. V. P., Beroncal, E. L., Baciu, C., Galasso, M., Gomes, B., Mariscal, A., Hough, O., Brambate, E., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abf7601 · Cited by 137 · see citing works
G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions
Santos, T. A. B. D., Salgado, G. F. J., Cabrita, E. J., & Cruz, C. (2021) · Pharmaceuticals · doi:10.3390/ph14080769 · Cited by 138 · see citing works
CircCD44 plays oncogenic roles in triple-negative breast cancer by modulating the miR-502–5p/KRAS and IGF2BP2/Myc axes
Li, J., Gao, X., Zhang, Z., Lai, Y., Lin, X., Lin, B., Ma, M., Liang, X., Li, X., Lv, W., et al. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01444-1 · Cited by 113 · see citing works
“The C-Myc-targeting strategy can be summarized as follows: 1) Targeting C-Myc transcription: stabilization of G-quadruplexes with small molecules such as QN-1 [33].”
Background
Ligand-induced native G-quadruplex stabilization impairs transcription initiationPreprint
Li, C., Wang, H., Yin, Z., Fang, P., Xiao, R., Xiang, Y., Wang, W., Li, Q., Huang, B., Huang, J., et al. (2021) · Genome Research · doi:10.1101/gr.275431.121 · Cited by 115 · see citing works
“However, this evidence is largely based on computationally predicted G4 motifs, correlations between G4 and gene expression, or manipulation of G4 structures on individual genes in plasmid constructs (Spiegel et al. 2020; Varshney et al. 2020).”
Background
Targeting MYCN in Pediatric and Adult Cancers
Liu, Z., Chen, S. S., Clarke, S., Veschi, V., & Thiele, C. J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.623679 · Cited by 94 · see citing works
Telomerase Regulation: A Role for Epigenetics
Doğan, F., & Forsyth, N. R. (2021) · Cancers · doi:10.3390/cancers13061213 · Cited by 104 · see citing works
Origin, Diversity, and Evolution of Telomere Sequences in Plants
Peška, V., & Garcia, S. (2020) · Frontiers in Plant Science · doi:10.3389/fpls.2020.00117 · Cited by 91 · see citing works
Viral G-quadruplexes: New frontiers in virus pathogenesis and antiviral therapy
Ruggiero, E., & Richter, S. (2020) · Annual Reports in Medicinal Chemistry · doi:10.1016/bs.armc.2020.04.001 · Cited by 89
“the large flat aromatic core that stacks on the G quartet, increasing discrimination among different G4s; high-molecular weights and positivecharged side chains, which guarantee loops and grooves interaction to the detriment of cellular uptake.(83) Indeed, low selectivity and poor drug-”
Background
Genome-wide mapping of i-motifs reveals their association with transcription regulation in live human cells
Zanin, I., Ruggiero, E., Nicoletto, G., Lago, S., Maurizio, I., Gallina, I., & Richter, S. N. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad626 · Cited by 101 · see citing works
How to untie G-quadruplex knots and why?
Lejault, P., Mitteaux, J., Sperti, F. R., & Monchaud, D. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.01.015 · Cited by 96 · see citing works
G4-quadruplex-binding proteins: review and insights into selectivity
Meier-Stephenson, V. (2022) · Biophysical Reviews · doi:10.1007/s12551-022-00952-8 · Cited by 85 · see citing works
A first-in-class clinical G-quadruplex-targeting drug. The bench-to-bedside translation of the fluoroquinolone QQ58 to CX-5461 (Pidnarulex)
Xu, H., & Hurley, L. H. (2022) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2022.129016 · Cited by 84 · see citing works
Rational Design of NIR-II G-Quadruplex Fluorescent Probes for Accurate In Vivo Tumor Metastasis Imaging.
Wang, R.-X., Ou, Y.-F., Chen, Y.-S., Ren, T.-B., Yuan, L., & Zhang, X.-B. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c13851 · Cited by 83 · see citing works
BODIPY based Metal-Organic Macrocycles and Frameworks: Recent Therapeutic Developments
Gupta, G., Sun, Y., Das, A., Stang, P., & Lee, C.-Y.-O. (2021) · Coordination chemistry reviews · doi:10.1016/j.ccr.2021.214308 · Cited by 81 · see citing works
Multimeric G-quadruplexes: A review on their biological roles and targeting
Frasson, I., Pirota, V., Richter, S. N., & Doria, F. (2022) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2022.01.197 · Cited by 91 · see citing works
G-quadruplex DNA: A Longer Story.
Monsen, R. C., Trent, J., & Chaires, J. (2022) · Accounts of Chemical Research · doi:10.1021/acs.accounts.2c00519 · Cited by 78
Identifying G-Quadruplex-DNA-Disrupting Small Molecules
Mitteaux, J., Lejault, P., Wojciechowski, F., Joubert, A., Boudon, J., Desbois, N., Gros, C. P., Hudson, R. H. E., Boulé, J.-B., Granzhan, A., et al. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c04426 · Cited by 107 · see citing works
G-Quadruplex-Binding Proteins: Promising Targets for Drug Design
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“In particular, the G4s in the promoter regions of the proto-oncogenes have been most intensively studied so far [2].”
BackgroundInfluential
Structural Basis of Pyridostatin and Its Derivatives Specifically Binding to G-Quadruplexes
Liu, L., Ma, T., Zeng, Y., Liu, W., & Mao, Z. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c04775 · Cited by 94 · see citing works
Targeting c-MYC G-Quadruplexes for Cancer Treatment with Small Molecules
Thumpati, P., Rai, S. N., Prajapati, C., Ramakrishna, K., & Singh, S. K. (2025) · Scientia Pharmaceutica · doi:10.3390/scipharm93010006 · Cited by 69 · see citing works
“Most of these molecules contain extended aromatic structures with planar and electron-deficient ring systems for π - π stacking with a G-quartet platform instead of intercalating among the stacked base pairs of the DNA, as known for many duplex DNA-binding ligands (Figure 2) [22,23].”
Treatment of Ovarian Cancer Beyond PARP Inhibition: Current and Future Options
Garg, V., & Oza, A. M. (2023) · Drugs · doi:10.1007/s40265-023-01934-0 · Cited by 67 · see citing works
“G4 unwinding proteins/helicases remove these G4 structures in normal cells [161, 162].”
Background
Recent advances on G-quadruplex for biosensing, bioimaging and cancer therapy
Xu, J., Jiang, R., He, H.-L., Ma, C.-B., & Tang, Z.-W. (2021) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2021.116257 · Cited by 69 · see citing works
On the Road to Fight Cancer: The Potential of G-Quadruplex Ligands as Novel Therapeutic Agents
Alessandrini, I., Recagni, M., Zaffaroni, N., & Folini, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115947 · Cited by 83 · see citing works
“, antibodies; fluorescent probes, aptamers) for cellular imaging [25], together with the ever growing repertoire of identified G4-interacting proteins [25,33], have undoubtedly represented an important step towards a better and more accurate characterization of G4 structures and their possible interaction with ligands…”
Background
Replication stress as a driver of cellular senescence and aging
Herr, L. M., Schaffer, E. D., Fuchs, K. F., Datta, A., & Brosh, R. M. (2024) · Communications Biology · doi:10.1038/s42003-024-06263-w · Cited by 68 · see citing works
Metal Ion Signaling in Biomedicine
Rodriguez, R., Müller, S., Colombeau, L., Solier, S., Sindikubwabo, F., & Cañeque, T. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00577 · Cited by 66 · see citing works
Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer
Long, W., Zheng, B.-X., Li, Y., Huang, X.-H., Lin, D.-M., Chen, C.-C., Hou, J.-Q., Ou, T.-M., Wong, W.-L., Zhang, K., et al. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac090 · Cited by 60 · see citing works
“The lateral loop and flanking bases are in the 5′ or 3′-terminal (13).”
Nucleic Acids and Their Analogues for Biomedical Applications
Wang, F., Li, P., Chu, H. C., & Lo, P. K. (2022) · Biosensors · doi:10.3390/bios12020093 · Cited by 81 · see citing works
“G-rich DNA strands can form G-quadruplex in the presence of cations and then dissociate by adding the ion-chelating ligands [28].”
Background
The Relevance of G-Quadruplexes for DNA Repair
Linke, R., Limmer, M., Juranek, S., Heine, A., & Paeschke, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212599 · Cited by 64 · see citing works
“Treatment with G4 ligands can induce DNA damage, micronuclei formation, DNA replication pausing, telomere defects and/or transcriptional changes (reviewed in [49]).”
Background
Affinity Sensors for the Diagnosis of COVID-19
Drobysh, M., Ramanavičienė, A., Viter, R., & Ramanavičius, A. (2021) · Micromachines · doi:10.3390/mi12040390 · Cited by 75 · see citing works
“These structures take part in crucial genome functions such as transcription, replication, and genome stability [81].”
Background
A Helicase Unwinds Hexanucleotide Repeat RNA G-quadruplexes and Facilitates Repeat-associated Non-AUG Translation
Liu, H., Lu, Y.-N., Paul, T., Periz, G., Banco, M., Ferré-D'Amaré, A., Rothstein, J., Hayes, L., Myong, S., & Wang, J.-O. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c00131 · Cited by 56
Roles of the RGG Domain and RNA Recognition Motif of Nucleolin in G-Quadruplex Stabilization
Masuzawa, T., & Oyoshi, T. (2020) · ACS Omega · doi:10.1021/acsomega.9b04221 · Cited by 56 · see citing works
Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine
Wang, K., Liu, Y., Li, J., Xiao, C., Wang, Y., Gu, W., Li, Y., Xia, Y., Yan, T., Yang, M.-H., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33761-4 · Cited by 64 · see citing works
Interactions of HMGB Proteins with the Genome and the Impact on Disease
Voong, C. K., Goodrich, J., & Kugel, J. F. (2021) · Biomolecules · doi:10.3390/biom11101451 · Cited by 54 · see citing works
“G4 structures form through the self-association of guanines to form stacked tetrads and could serve to regulate cellular processes that occur on the genome [79,80].”
Background
The beginning and the end: flanking nucleotides induce a parallel G-quadruplex topology
Chen, J., Cheng, M., Salgado, G. F. J., Stadlbauer, P., Zhang, X., Amrane, S., Guédin, A., He, F., Šponer, J., Ju, H., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab681 · Cited by 59 · see citing works
“The topology of the G4 core may be parallel, antiparallel or hybrid, which provides a basis for the specific recognition by ligands and functional regulation, but also complicates structural and biophysical predictions (3,5).”
Background
Mechanical Properties of DNA Hydrogels: Towards Highly Programmable Biomaterials
Bush, J., Hu, C.-H., & Veneziano, R. (2021) · Applied Sciences · doi:10.3390/app11041885 · Cited by 52
Chem-map profiles drug binding to chromatin in cells
Yu, Z., Spiegel, J., Melidis, L., Hui, W. W. I., Zhang, X., Radzevičius, A., & Balasubramanian, S. (2023) · Nature Biotechnology · doi:10.1038/s41587-022-01636-0 · Cited by 61 · see citing works
Self-citation
Critical Design Factors for Electrochemical Aptasensors Based on Target-Induced Conformational Changes: The Case of Small-Molecule Targets
Onaş, A. M., Dascalu, C., Raicopol, M., & Pilan, L. (2022) · Biosensors · doi:10.3390/bios12100816 · Cited by 51
Corroles at work: a small macrocycle for great applications.
di Natale', C., Gros, C., & Paolesse, R. (2022) · Chemical Society Reviews · doi:10.1039/d1cs00662b · Cited by 51
2'-Fluoro-arabinonucleic Acid (FANA): A Versatile Tool for Probing Biomolecular Interactions.
El-Khoury, R., & Damha, M. (2021) · Accounts of Chemical Research · doi:10.1021/acs.accounts.1c00125 · Cited by 51 · see citing works
Recent Developments in G-Quadruplex Binding Ligands and Specific Beacons on Smart Fluorescent Sensor for Targeting Metal Ions and Biological Analytes.
Zhao, L., Ahmed, F., Zeng, Y., Xu, W.-Q., & Xiong, H. (2022) · ACS Sensors · doi:10.1021/acssensors.2c00992 · Cited by 50
Quadruplex Ligands in Cancer Therapy
Sánchez-Martín, V., Soriano, M., & Garcia-Salcedo, J. A. (2021) · Cancers · doi:10.3390/cancers13133156 · Cited by 60 · see citing works
“Altogether this evidence suggests that quadruplexes are involved in the regulation of different biological pathways such as replication, transcription, translation, and genome instability [23] (Figure 2A).”
Background
Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models.
Ahmed, A., Angell, R., Oxenford, S., Worthington, J., Williams, N., Barton, N., Fowler, T. G., O'Flynn, D. E., Sunose, M., McConville, M., et al. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00317 · Cited by 50 · see citing works
Genome-wide analysis of 8-oxo-7,8-dihydro-2'-deoxyguanosine at single-nucleotide resolution unveils reduced occurrence of oxidative damage at G-quadruplex sites
An, J., Yin, M., Yin, J., Wu, S., Selby, C. P., Yang, Y., Sancar, A., Xu, G.-L., Qian, M., & Hu, J. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab1022 · Cited by 49 · see citing works
“A G4 is a four-stranded noncanonical DNA secondary structure formed in G-rich regions such as telomeres and promoters (17).”
Advances in Functional Nucleic Acid SERS Sensing Strategies.
Shi, L., Liu, Y.-K., Li, X., Zhang, H.-J., Wang, Z., He, S., Fan, D., Huang, X., Zi, Y., Han, Y.-P., et al. (2025) · ACS Sensors · doi:10.1021/acssensors.4c02611 · Cited by 48 · see citing works
G-Quadruplexes in c-MYC Promoter as Targets for Cancer Therapy
Bahls, B., Aljnadi, I. M., Emídio, R. M., Mendes, E., & Paulo, A. (2023) · Biomedicines · doi:10.3390/biomedicines11030969 · Cited by 48 · see citing works
Recent Developments in Small-Molecule Ligands of Medicinal Relevance for Harnessing the Anticancer Potential of G-Quadruplexes
Savva, L., & Georgiades, S. N. (2021) · Molecules · doi:10.3390/molecules26040841 · Cited by 56 · see citing works
“The stabilization of a G-quadruplex in the human telomere induces telomere shortening and apoptosis or senescence of tumor cells [106], consistent with telomerase function impairment [107].”
Background
CRISPR-Cas12a trans-cleaves DNA G-quadruplexes.
Li, Y., Li, T., Liu, B.-F., Hu, R., Zhu, J., He, T., Zhou, X., Li, C.-N., Yang, Y.-H., & Liu, M. (2020) · Chemical Communications · doi:10.1039/d0cc05540a · Cited by 48 · see citing works
Identification and targeting of G-quadruplex structures in MALAT1 long non-coding RNA
Mou, X., Liew, S. W., & Kwok, C.-K. (2021) · bioRxiv · doi:10.1093/nar/gkab1208 · Cited by 46 · see citing works
Detection of alternative DNA structures and its implications for human disease
Matos-Rodrigues, G. E., Hisey, J. A., Nussenzweig, A., & Mirkin, S. M. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.08.018 · Cited by 65 · see citing works
Folding dynamics of polymorphic G‐quadruplex structures
Grün, J. T., & Schwalbe, H. (2021) · Biopolymers · doi:10.1002/bip.23477 · Cited by 52 · see citing works
Whole Genome Identification of Potential G-Quadruplexes and Analysis of the G-Quadruplex Binding Domain for SARS-CoV-2
Zhang, R., Xiao, K., Gu, Y., Liu, H., & Sun, X. S. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.587829 · Cited by 49 · see citing works
Major Achievements in the Design of Quadruplex-Interactive Small Molecules
Mendes, E., Aljnadi, I. M., Bahls, B., Victor, B., & Paulo, A. (2022) · Pharmaceuticals · doi:10.3390/ph15030300 · Cited by 43 · see citing works
“Since then, G4s were shown to form not only in vitro but also in cells [6,7], in the entire genome, even though quadruplex-forming sequences are particularly enriched in telomeres, gene promoters, and other untranslated regions of the genome [8].”
Background
Interactions of small molecules with DNA junctions
McQuaid, K. T., Pipier, A., Cardin, C. J., & Monchaud, D. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac1043 · Cited by 54 · see citing works
Programmable DNA hydrogels construction with functional regulations for biosensing applications
Yan, C., Hua, Y.-L., Guo, J.-R., & Miao, P. (2024) · Trends in Analytical Chemistry (TrAC) · doi:10.1016/j.trac.2024.117628 · Cited by 41
Gallic Acid: A Natural Phenolic Compound Exerting Antitumoral Activities in Colorectal Cancer via Interaction with G-Quadruplexes
Sánchez-Martín, V., Plaza‐Calonge, M. D. C., Soriano‐Lerma, A., Ortiz-González, M., Linde-Rodríguez, Á., Pérez‐Carrasco, V., Ramírez-Macías, I., Cuadros, M., Fernández, J. G., Murciano‐Calles, J., et al. (2022) · Cancers · doi:10.3390/cancers14112648 · Cited by 43 · see citing works
“G4s are four-stranded, noncanonical secondary structures formed via Hoogsteen hydrogenbonding of four guanines in planar quartets thatself-stack [9].”
Background
Beyond the double helix: DNA structural diversity and the PDB
Neidle, S. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100553 · Cited by 41
Multifaceted Role of PARP1 in Maintaining Genome Stability Through Its Binding to Alternative DNA Structures
Laspata, N., Muoio, D., & Fouquerel, E. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168207 · Cited by 40 · see citing works
Stability prediction of canonical and non-canonical structures of nucleic acids in various molecular environments and cells.
Takahashi, S., & Sugimoto, N. (2020) · Chemical Society Reviews · doi:10.1039/d0cs00594k · Cited by 40 · see citing works
Intricate 3D architecture of a DNA mimic of GFP
Passalacqua, L. F. M., Banco, M., Moon, J., Li, X., Jaffrey, S., & Ferré-D'Amaré, A. (2023) · Nature · doi:10.1038/s41586-023-06229-8 · Cited by 39
Monohydrazone Based G-Quadruplex Selective Ligands Induce DNA Damage and Genome Instability in Human Cancer Cells
Amato, J., Miglietta, G., Morigi, R., Iaccarino, N., Locatelli, A., Leoni, A., Novellino, E., Pagano, B., Capranico, G., & Randazzo, A. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01866 · Cited by 44 · see citing works
DNA folds threaten genetic stability and can be leveraged for chemotherapy
Zell, J., Sperti, F. R., Britton, S., & Monchaud, D. (2020) · RSC Chemical Biology · doi:10.1039/d0cb00151a · Cited by 58 · see citing works
DeepG4: A deep learning approach to predict cell-type specific active G-quadruplex regions
Rocher, V., Genais, M., Nassereddine, E., & Mourad, R. (2021) · PLoS Comput. Biol. · doi:10.1371/journal.pcbi.1009308 · Cited by 37 · see citing works
“G4 can be formed of DNA [5] or RNA [6].”
Background
Metal-Based G-Quadruplex Binders for Cancer Theranostics
Palma, E., Carvalho, J., Cruz, C., & Paulo, A. (2021) · Pharmaceuticals · doi:10.3390/ph14070605 · Cited by 44 · see citing works
“reported a series of Re(I)–tricarbonyl complexes containing the facially coordinated [1,4,7]-triazacyclononane (TACN) ligand, which was covalently linked to a porphyrin scaffold that can act as a photosensitizer (PS) and also as a π-stacking core to achieve G4 selectivity [151].”
Background
Water spines and networks in G-quadruplex structures
Li, K., Yatsunyk, L., & Neidle, S. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1177 · Cited by 37
Phthalocyanines for G-quadruplex aptamers binding.
Lopes-Nunes, J., Carvalho, J., Figueiredo, J., Ramos, C., Lourenço, L. M. O., Tomé, J. P. C., Neves, M., Mergny, J., Queiroz, J., Salgado, G., et al. (2020) · Bioorganic chemistry (Print) · doi:10.1016/j.bioorg.2020.103920 · Cited by 37
G-quadruplex–stalled eukaryotic replisome structure reveals helical inchworm DNA translocation
Batra, S., Allwein, B., Kumar, C., Devbhandari, S., Brüning, J.-G., Bahng, S., Lee, C. M., Marians, K. J., Hite, R. K., & Remus, D. (2025) · Science · doi:10.1126/science.adt1978 · Cited by 42 · see citing works
G-quadruplexes in cancer-related gene promoters: from identification to therapeutic targeting
Romano, F., Porzio, A. D., Iaccarino, N., Riccardi, G., Lorenzo, R. D., Laneri, S., Pagano, B., Amato, J., & Randazzo, A. (2023) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2023.2271168 · Cited by 41 · see citing works
“Among these non-canonical DNA conformations, G4s are by far the most extensively investigated structures due to their role in peculiar regions of the genome [6].”
BackgroundInfluential
Current Developments of N-Heterocyclic Carbene Au(I)/Au(III) Complexes toward Cancer Treatment
Tialiou, A., Chin, J. M., Keppler, B., & Reithofer, M. R. (2022) · Biomedicines · doi:10.3390/biomedicines10061417 · Cited by 36
Global mapping of RNA G-quadruplexes (G4-RNAs) using G4RP-seq
Yang, S. Y., Monchaud, D., & Wong, J. M. Y. (2022) · Nature Protocols · doi:10.1038/s41596-021-00671-6 · Cited by 36
“(2) Cells are cross-linked using formaldehyde.”
ONQUADRO: a database of experimentally determined quadruplex structures
Zok, T., Kraszewska, N., Miskiewicz, J., Pielacinska, P., Zurkowski, M., & Szachniuk, M. (2021) · Nucleic Acids Res. · doi:10.1093/nar/gkab1118 · Cited by 36 · see citing works
“A complete G4 is assembled from at least two G-tetrads stacked one above another, and is stabilised by monovalent cations located in the ion channel (5,9).”
Cellular Visualization of G-Quadruplex RNA via Fluorescence- Lifetime Imaging Microscopy
Robinson, J., Stenspil, S. G., Maleckaitė, K., Bartlett, M., di Antonio, M., Vilar, R., & Kuimova, M. (2023) · bioRxiv · doi:10.1021/jacs.3c11908 · Cited by 35
Predicting Genetic Disorder and Types of Disorder Using Chain Classifier Approach
Raza, A., Rustam, F., Siddiqui, H., Díez, I. D. L. T., Soto, B. G.-Z., Lee, E., & Ashraf, I. (2022) · Genes · doi:10.3390/genes14010071 · Cited by 35
“There are several genetic disorders: single gene inheritance disorders [4], chromosomal disorders or mitochondrial genetic inheritance disorders [5], and complex disorders or multifactorial genetic inheritance disorders [6] and they are examined based on the DNA structure [7].”
Background
Expanding the Toolbox of Target Directed Bio-Orthogonal Synthesis: In Situ Direct Macrocyclization by DNA Templates.
Chaudhuri, R., Prasanth, T., & Dash, J. (2022) · Angewandte Chemie · doi:10.1002/anie.202215245 · Cited by 35 · see citing works
Zuo1 supports G4 structure formation and directs repair toward nucleotide excision repair
Magis, A. D., Götz, S., Hajikazemi, M., Fekete-Szücs, E., Caterino, M., Juranek, S., & Paeschke, K. (2020) · Nature Communications · doi:10.1038/s41467-020-17701-8 · Cited by 53 · see citing works
Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
Grange, L., Reynolds, J., Ullah, F., Isidor, B., Shearer, R. F., Latypova, X., Baxley, R. M., Oliver, A., Ganesh, A., Cooke, S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34349-8 · Cited by 34 · see citing works
Parallel G-quadruplexes recruit the HSV-1 transcription factor ICP4 to promote viral transcription in herpes virus-infected human cells
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“G4s are known to play important roles in several biological processes, such as DNA replication, damage response, RNA transcription and processing, transcriptional and translational regulation and others (Spiegel et al., 2020).”
Background
Understanding The Role of Reline, a Natural DES, on Temperature-Induced Conformational Changes of C-Kit G-Quadruplex DNA: A Molecular Dynamics Study
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“…strands have the same direction and the fourth is oriented oppositely ( Moreover, G4 structures can be intramolecular, originating from a single nucleotide sequence, or bimolecular or tetramolecular, involving the intermolecular interaction of two or four nucleotide filaments, respectively [8].”
Background
Unraveling the Complexity of DNA Radiation Damage Using DNA Nanotechnology
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Authors: Spiegel, J., Adhikari, S., & Balasubramanian, S.
Affiliations: Cancer Research UK (GB)
University of Cambridge (GB)
Corresponding author: Balasubramanian, Shankar
ORCID: Spiegel, Jochen
Adhikari, Santosh
Balasubramanian, Shankar
Venue: Trends in Chemistry
Publisher: Elsevier BV
Published: 2020-02
Volume: 2
Issue: 2
Pages: 123-136
ISSN: 2589-5974 (ISSN-L)
DOI: 10.1016/j.trechm.2019.07.002
PMC: PMC7472594
OpenAlex: W2966334511
Cited by: 920
References: 121
Citations by year: 2026: 111 · 2025: 157 · 2024: 158 · 2023: 144 · 2022: 151 · 2021: 122 · 2020: 74 · 2019: 2
FWCI: 7.73
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Trends in Chemistry (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
Apollo
Funders: Wellcome Trust
Cancer Research UK
Horizon 2020 Framework Programme
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
Keywords: G-quadruplex, guanine-rich DNA, genome stability, transcription, DNA replication, epigenetic regulation, cancer, G-quadruplex-binding proteins

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The Structure and Function of DNA G-Quadruplexes

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