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

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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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Figure 1 G-Quadruplex (G4) Structures. (A) Structure of a G-quartet formed by the Hoogsteen hydrogen-bonded guanines and central cation (coloured green) coordinated to oxygen atoms. Crystal structure of human telomeric G4s (Protein Data Bank: 1KF1): (B) top view and (C) side view; backbone is represented by grey tube and the structures are colour-coded by atoms. Schematic representation of unimolecular G4s based on the strand direction: (D) parallel, (E) anti-parallel, and (F) hybrid with a bulge.CC BY-NC-ND · PubMed Central

Figure 2 G-Quadruplex (G4) Ligands. (A) Crystal structure of a naphthalene diimide, MM41 bound to an intramolecular human telomeric DNA G4, colour-coded by atoms; water molecules are shown as red spheres, MM41 carbon atoms are coloured green, surface of the G4 is coloured light grey (Protein Data Bank: 3UYH). (B) Structures of selected widely used G4 ligands.CC BY-NC-ND · PubMed Central

Figure 3 Detection and Mapping of DNA G-Quadruplexes (G4s). (A) Visualisation of G4s in fixed or live cells using structure-specific antibodies as well as labelled or intrinsically fluorescent G4 ligands. The number of detected G4 foci can be increased by small molecule treatment or helicase depletion. (B) High-throughput sequencing of G4s in human genomic DNA (G4-Seq). Two consecutive sequencing runs, under normal and G4 stabilising conditions, provide a reference map and detect G4-dependent polymerase stalling, respectively. (C) Chromatin immunoprecipitation employing antibodies against endogenous G4-binding proteins followed by next-generation sequencing (ChIP-seq). Genomic occupancy of endogenous proteins is used to infer putative G4 sites. (D) Treatment with G4 ligands induces G4-dependent DNA damage. ChIP-seq of DNA damage markers in combination with deep sequencing detects G4-associated regions. (E) Permanganate oxidation of nucleotides in transiently unwound regions traps the unpaired state, resulting in sensitivity to a single-strand specific nuclease. Computational prediction is then used to infer the type of underlying non-B-DNA structures based on sequence context. (F) G4-specific chromatin immunoprecipitation and next-generation sequencing (G4 ChIP-seq). A G4-specific antibody (e.g., BG4) is used to precipitate G4 structures directly from native chromatin and is identified by deep sequencing.CC BY-NC-ND · PubMed Central

Figure 4 Crystal Structure of DHX36 Bound to the c-Myc G4 (Protein Data Bank: 5VHE). Overall structure is shown in cartoon representation with the domain organisation of DHX36 colour-coded (top). The α-helical DHX36-specific motif (DSM) stacks on the 5′-quartet. The residues Ile65, Tyr69, and Ala70 form a nonpolar surface similar to the proposed binding mode of most small molecule G-quadruplex (G4) ligands (bottom).CC BY-NC-ND · PubMed Central

Figure 5 G-Quadruplex (G4) Can Induce Epigenetic Reprogramming. Unresolved G4 structures (e.g., G4 ligand treatment, impaired helicases) on the leading strand may promote uncoupling of DNA synthesis from opening of the replication fork and disrupt histone recycling. Original histone modifications (blue) are lost and replaced with new histones (brown), resulting in epigenetic reprogramming upstream of G4 sites.CC BY-NC-ND · PubMed Central

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RETRACTED: Real-time monitoring of DNA G-quadruplexes in living cells with a small-molecule fluorescent probe
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Method
Unraveling cell type–specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs
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BackgroundInfluential
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Permanganate/S1 Nuclease Footprinting Reveals Non-B DNA Structures with Regulatory Potential across a Mammalian Genome
Kouzine, F., Wójtowicz, D., Baranello, L., Yamane, A., Nelson, S., Resch, W., Kieffer-Kwon, K.-R., Benham, C. J., Casellas, R. C., Przytycka, T. M., et al. (2017) · Cell Systems · doi:10.1016/j.cels.2017.01.013 · Cited by 215 · cited 2×
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Structure of the first parallel DNA quadruplex-drug complex.
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BackgroundInfluential
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 189
G-quadruplex DNA drives genomic instability and represents a targetable molecular abnormality in ATRX-deficient malignant glioma
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G-quadruplex unwinding helicases and their function in vivo
Sauer, M., & Paeschke, K. (2017) · Biochemical Society Transactions · doi:10.1042/bst20170097 · Cited by 179
Human replication protein A unfolds telomeric G-quadruplexes
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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 177 · cited 5×
“G4 ligands such as pyridostatin and RHPS4 cause DNA double-strand breaks in cancer cells and activate DNA repair pathways [47,117].”
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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×
“recognise and unwind the MYC promoter G4 [78].”
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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 168 · cited 1×
“org/) [32], with some examples of widely used ligands”
Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule
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“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].”
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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×
“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
Replication of G Quadruplex DNA
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“Various models have been postulated for the biological role of G4 structures during DNA replication [100,101].”
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A quantitative mass spectrometry-based approach to monitor the dynamics of endogenous chromatin-associated protein complexes
Papachristou, E. K., Kishore, K., Holding, A. N., Harvey, K., Roumeliotis, T. I., Chilamakuri, C. S. R., Omarjee, S., Chia, K. M., Swarbrick, A., Lim, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04619-5 · Cited by 155 · cited 1×
“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”
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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×
“availability of large datasets on G4 formation has enabled the application of machine learning to predict G4 forming propensity [19].”
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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×
“in their promoter region, corroborating a link between G4s and transcription [107,108].”
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. E. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp138 · Cited by 154 · cited 1×
“and HRAS promoter G4 in vitro, respectively [80,81].”
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. N., Reszka, A. P., & Neidle, S. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks023 · Cited by 149 · cited 1×
“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].”
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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×
“Various models have been postulated for the biological role of G4 structures during DNA replication [100,101].”
Background
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 148 · cited 1×
“telomeric G4 structure formation was observed to be dynamically controlled through protein interactions in a cell cycle-dependent manner [39,40].”
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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×
“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
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
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 143
The KRAS Promoter Responds to Myc-associated Zinc Finger and Poly(ADP-ribose) Polymerase 1 Proteins, Which Recognize a Critical Quadruplex-forming GA-element*
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“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
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
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 132 · cited 1×
“in their promoter region, corroborating a link between G4s and transcription [107,108].”
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×
“G4 signals were found at transcription start sites, in introns and intergenic regions [44].”
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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
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×
“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 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., Chen, S.-B., & Huang, Z. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b09329 · Cited by 110 · cited 1×
“domains were compared to predict new putative G4 interactors [67,68].”
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 107
Single-molecule imaging reveals a common mechanism shared by G-quadruplex–resolving helicases
Tippana, R., Hwang, H. H., Opresko, P. L., Bohr, V. A., & Myong, S. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1603724113 · Cited by 106
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
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×
“of G4 structures induced replication-dependent loss of epigenetic information showing that G4s can serve as obstacles to the replicationmachinery [104].”
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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×
“and HRAS promoter G4 in vitro, respectively [80,81].”
Background
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 99
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 92
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×
“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×
“Further considerations include the effects of molecular crowding [20] and DNA base modifications, such as cytosine methylation [21] and guanine oxida-”
Background
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 79 · cited 1×
“consensus sequences for hundreds of nuclear proteins in parallel [69].”
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. N. (1993) · Biochemistry · doi:10.1021/bi00073a021 · Cited by 76 · cited 1×
“Further considerations include the effects of molecular crowding [20] and DNA base modifications, such as cytosine methylation [21] and guanine oxida-”
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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 76 · cited 1×
“[98] and to promote telomerase activity [99].”
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×
“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].”
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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., & Pečínka, P. (2018) · Molecules · doi:10.3390/molecules23092341 · Cited by 69
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
Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
Sengar, A., Vandana, J. J., Chambers, V. S., Antonio, M. D., Winnerdy, F. R., Balasubramanian, S., & Phan, A. T. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky1179 · Cited by 61 · 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].”
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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].”
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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
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 57 · cited 1×
“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
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 55 · cited 1×
“Werner (WRN) helicases, albeit with different substrate specificity, and showed the capacity to displace G4-stabilising ligands [71,72].”
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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 50 · cited 1×
“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×
“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
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.”
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See all 920

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
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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