Single-stranded guanine-rich DNA sequences can fold into four-stranded DNA structures called G-quadruplexes (G4s) that arise from the self-stacking of two or more guanine quartets. There has been considerable recent progress in the detection and mapping of G4 structures in the human genome and in biologically relevant contexts. These advancements, many of which align with predictions made previously in computational studies, provide important new insights into the functions of G4 structures in, for example, the regulation of transcription and genome stability, and uncover their potential relevance for cancer therapy.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Davis, J. T. G-Quartets 40 years later: from 5′-GMP to molecular biology and supramolecular chemistry. Angew. Chem. Int. Ed. 43, 668–698 (2004).
Rhodes, D. & Lipps, H. J. G-Quadruplexes and their regulatory roles in biology. Nucleic Acid. Res. 43, 8627–8637 (2015).
Bochman, M. L., Paeschke, K. & Zakian, V. A. DNA secondary structures: stability and function of G-quadruplex structures. Nat. Rev. Genet. 11, 770–780 (2012).
Huppert, J. L. & Balasubramanian, S. Prevalence of quadruplexes in the human genome. Nucleic Acid. Res. 33, 2908–2916 (2005).
Todd, A. K., Johnston, M. & Neidle, S. Highly prevalent putative quadruplex sequence motif in human DNA. Nucleic Acid. Res. 33, 2901–2907 (2005).
Bedrat, A., Lacroix, L. & Mergny, J.-L. Re-evaluation of G-quadruplex propensity with G4Hunter. Nucleic Acid. Res. 44, 1746–1759 (2016).
Schaffitzel, C. et al. In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei. Proc. Natl Acad. Sci. USA 98, 8572–8577 (2001).
Paeschke, K. et al. Telomerase recruitment by the telomere end binding protein-β facilitates G-quadruplex DNA unfolding in ciliates. Nat. Struct. Mol. Biol. 15, 598–604 (2008).
Biffi, G., Tannahill, D., McCafferty, J. & Balasubramanian, S. Quantitative visualization of DNA G-quadruplex structures in human cells. Nat. Chem. 5, 182–186 (2013).
Henderson, A. et al. Detection of G-quadruplex DNA in mammalian cells. Nucleic Acid. Res. 42, 860–869 (2014).
Moye, A. L. et al. Telomeric G-quadruplexes are a substrate and site of localization for human telomerase. Nat. Commun. 6, 7643 (2015).
Zahler, A. M. Williamson, J. R. Cech, T. R. & Prescott, D. M. Inhibition of telomerase by G-quartet DNA structures. Nature 350, 718–720 (1991).
Rodriguez, R. et al. Small-molecule-induced DNA damage identifies alternative DNA structures in human genes. Nat. Chem. Biol. 8, 301–310 (2012).
Huang, W. C. et al. Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents. Nucleic Acid. Res. 43, 10102–10113 (2015).
Shivalingam, A. et al. The interactions between a small molecule and G-quadruplexes are visualized by fluorescence lifetime imaging microscopy. Nat. Commun. 6, 8178 (2015).
Granotier, C. et al. Preferential binding of a G-quadruplex ligand to human chromosome ends. Nucleic Acid. Res. 33, 4182–4190 (2005).
Hänsel-Hertsch, R. et al. G-Quadruplex structures mark human regulatory chromatin. Nat. Genet. 48, 1267–1272 (2016).
Chambers, V. S. et al. High-throughput sequencing of DNA G-quadruplex structures in the human genome. Nat. Biotechnol. 33, 877–881 (2015).
Gray, L. T., Vallur, A. C., Eddy, J. & Maizels, N. G-Quadruplexes are genomewide targets of transcriptional helicases XPB and XPD. Nat. Chem. Biol. 10, 313–318 (2014).
Law, M. J. et al. ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell 143, 335–336 (2010).
Paeschke, K., Capra, J. A. & Zakian, V. A. DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase. Cell 145, 678–691 (2011).
Kanoh, Y. et al. Rif1 binds to G-quadruplexes and suppresses replication over long distances. Nat. Struct. Mol. Biol. 22, 889–897 (2015).
Siddiqui-Jain, A., Grand, C. L., Bearss, D. J. & Hurley, L. H. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. Proc. Natl Acad. Sci. USA 99, 11593–11598 (2002).
Cogoi, S. & Xodo, L. E. G-Quadruplex formation within the promoter of the KRAS proto-oncogene and its effect on transcription. Nucleic Acid. Res. 34, 2536–2549 (2006).
David, A. P. et al. G-Quadruplexes as novel cis-elements controlling transcription during embryonic development. Nucleic Acid. Res. 43, 4163–4173 (2015).
Johnson, J. E., Cao, K., Ryvkin, P., Wang, L. S. & Johnson, F. B. Altered gene expression in the Werner and Bloom syndromes is associated with sequences having G-quadruplex forming potential. Nucleic Acid. Res. 38, 1114–1122 (2010).
Nguyen, G. H. et al. Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs. Proc. Natl Acad. Sci. USA 111, 9905–9910 (2014).
Tang, W. et al. The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Hum. Mol. Genet. 25, 2060–2069 (2016).
Hoffmann, R. F. et al. Guanine quadruplex structures localize to heterochromatin. Nucleic Acid. Res. 43, 152–163 (2015).
Eckdahl, T. T. & Anderson, J. N. Conserved DNA structures in origins of replication. Nucleic Acid. Res. 18, 1609–1612 (1990).
Besnard, E. et al. Unraveling cell type-specific and reprogrammable human replication origin signatures associated with G-quadruplex consensus motifs. Nat. Struct. Mol. Biol. 19, 837–844 (2012).
Hoshina, S. et al. Human origin recognition complex binds preferentially to G-quadruplex-preferable RNA and single-stranded DNA. J. Biol. Chem. 288, 30161–30171 (2013).
Ribeyre, C. et al. The yeast Pif1 helicase prevents genomic instability caused by G-quadruplex-forming CEB1 sequences in vivo. PLoS Genet. 5, e1000475 (2009).
Paeschke, K. et al. Pif1 family helicases suppress genome instability at G-quadruplex motifs. Nature 497, 458–462 (2013).
Vannier, J. B., Pavicic-Kaltenbrunner, V., Petalcorin, M. I., Ding, H. & Boulton, S. J. RTEL1 dismantles T loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149, 795–806 (2012).
Mendoza, O., Bourdoncle, A., Boulé, J. B., Brosh, R. M. Jr & Mergny, J.-L. G-Quadruplexes and helicases. Nucleic Acid. Res. 44, 1989–2006 (2016).
Sarkies, P., Reams, C., Simpson, L. J. & Sale, J. E. Epigenetic instability due to defective replication of structured DNA. Mol. Cell 40, 703–713 (2010).
Schiavone, D. et al. Determinants of G quadruplex-induced epigenetic instability in REV1-deficient cells. EMBO J. 33, 2507–25020 (2014).
Piazza, A. et al. Genetic instability triggered by G-quadruplex interacting Phen-DC compounds in Saccharomyces cerevisiae. Nucleic Acid. Res. 38, 4337–4348 (2010).
Piazza, A. et al. Short loop length and high thermal stability determine genomic instability induced by G-quadruplex forming minisatellites. EMBO J. 34, 1718–1734 (2015).
Biffi, G., Tannahill, D., Miller, J., Howat, W. J. & Balasubramanian, S. Elevated levels of G-quadruplex formation in human stomach and liver cancer tissues. PLoS ONE 9, e102711 (2014).
Ohnmacht, S. A. et al. A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer. Sci. Rep. 5, 11385 (2015).
Salvati, E. et al. PARP1 is activated at telomeres upon G4 stabilization: possible target for telomere-based therapy. Oncogene 29, 6280–6293 (2010).
Aggarwal, M., Sommers, J. A., Shoemaker, R. H. & Brosh, R. M. Jr. Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress. Proc. Natl Acad. Sci. USA 108, 1525–1530 (2011).
McLuckie, K. I. et al. G-Quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells. J. Am. Chem. Soc. 135, 9640–9642 (2013).
Zimmer, J. et al. Targeting BRCA1 and BRCA2 deficiencies with G-quadruplex-interacting compounds. Mol. Cell 61, 449–460 (2016).
The Balasubramanian laboratory is core-funded by Cancer Research UK (C14303/A17197) and further supported by a Cancer Research UK programme grant (C9681/A18618). S.B. is a Wellcome Trust Senior Investigator (099232/Z/12/Z).
The authors declare no competing financial interests.
About this article
Cite this article
Hänsel-Hertsch, R., Di Antonio, M. & Balasubramanian, S. DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nat Rev Mol Cell Biol 18, 279–284 (2017). https://doi.org/10.1038/nrm.2017.3
Novel complexes with ONNO tetradentate coumarin schiff-base donor ligands: x-ray structures, DFT calculations, molecular dynamics and potential anticarcinogenic activity
Subtle Structural Changes of Dyes Lead to Distinctly Different Fluorescent Behaviors in Cellular Context: The Role of G-Quadruplex DNA Interaction Using Coumarin–Quinazolinone Conjugates as a Case Study
Analytical Chemistry (2021)
Current Opinion in Chemical Biology (2021)
RSC Chemical Biology (2021)
RNA Biology (2021)