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Crystal structure of parallel quadruplexes from human telomeric DNA

Nature volume 417, pages 876–880 (2002)Cite this article

Abstract

Telomeric ends of chromosomes, which comprise noncoding repeat sequences of guanine-rich DNA, are fundamental in protecting the cell from recombination and degradation1. Disruption of telomere maintenance leads to eventual cell death, which can be exploited for therapeutic intervention in cancer. Telomeric DNA sequences can form four-stranded (quadruplex) structures2,3,4, which may be involved in the structure of telomere ends5. Here we describe the crystal structure of a quadruplex formed from four consecutive human telomeric DNA repeats and grown at a K+ concentration that approximates its intracellular concentration. K+ ions are observed in the structure. The folding and appearance of the DNA in this intramolecular quadruplex is fundamentally different from the published Na+-containing quadruplex structures2,4,6. All four DNA strands are parallel, with the three linking trinucleotide loops positioned on the exterior of the quadruplex core, in a propeller-like arrangement. The adenine in each TTA linking trinucleotide loop is swung back so that it intercalates between the two thymines. This DNA structure suggests a straightforward path for telomere folding and unfolding, as well as ways in which it can recognize telomere-associated proteins.

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Figure 1: Schematic diagram of human telomeric quadruplex folding topologies.
Figure 2: The overall folding topology of the two 12-mers constituting the content of the asymmetric unit in the dimeric quadruplex.
Figure 3: Overall folding topology of the 22-mer intramolecular G-quadruplex.
Figure 4: Visualizations of the 22-mer and potential 22-mer repeats.

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References

  1. Hackett, J. A., Feldser, D. M. & Greider, C. W. Telomere dysfunction increases mutation rate and genomic instability. Cell 106, 275–286 (2001)

    Article  CAS  Google Scholar 

  2. Smith, F. W. & Feigon, J. Quadruplex structure of oxytricha telomeric DNA oligonucleotides. Nature 356, 164–168 (1992)

    Article  ADS  CAS  Google Scholar 

  3. Wang, Y. & Patel, D. J. Guanine residues in d(T2AG3) and d(T2G4) form parallel-stranded potassium cation stabilized G-quadruplexes with anti glycosidic torsion angles in solution. Biochemistry 31, 8112–8119 (1992)

    Article  CAS  Google Scholar 

  4. Horvath, M. P. & Schultz, S. C. DNA G-quartets in a 1.86 Å resolution structure of an Oxytricha nova telomeric protein–DNA complex. J. Mol. Biol. 310, 367–377 (2001)

    Article  CAS  Google Scholar 

  5. 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)

    Article  ADS  CAS  Google Scholar 

  6. Wang, Y. & Patel, D. J. Solution structure of the human telomeric repeat d[AG3(T2AG3)3] G-tetraplex. Structure 1, 263–282 (1993)

    Article  CAS  Google Scholar 

  7. Wright, W. E. et al. Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev. 11, 2801–2809 (1997)

    Article  CAS  Google Scholar 

  8. Simonsson, T. G-quadruplex DNA structures—variations on a theme. Biol. Chem. 382, 621–628 (2001)

    Article  CAS  Google Scholar 

  9. Phillips, K., Dauter, Z., Murchie, A. I., Lilley, D. M. & Luisi, B. The crystal structure of a parallel-stranded guanine tetraplex at 0.95 Å resolution. J. Mol. Biol. 273, 171–182 (1997)

    Article  CAS  Google Scholar 

  10. Mergny, J.-L. & Hélène, C. G-quadruplex DNA: a target for drug design. Nature Genet. 4, 1366–1367 (1998)

    Article  CAS  Google Scholar 

  11. Bearss, D. J., Hurley, L. H. & Von Hoff, D. D. Telomere maintenance mechanisms as a target for drug development. Oncogene 19, 6632–6641 (2000)

    Article  CAS  Google Scholar 

  12. Gowan, S. M. et al. A G-Quadruplex-interactive potent small-molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol. Pharmacol. 61, 1154–1162 (2002)

    Article  CAS  Google Scholar 

  13. Read, M. A. et al. Structure-based design of selective and potent G quadruplex-mediated telomerase inhibitors. Proc. Natl Acad. Sci. USA 98, 4844–4849 (2001)

    Article  ADS  CAS  Google Scholar 

  14. Sun, H., Yabuki, A. & Maizels, N. A human nuclease specific for G4 DNA. Proc. Natl Acad. Sci. USA 98, 12444–12449 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Li, J.-L. et al. Inhibition of the Bloom's and Werner's syndrome helicases by G-quadruplex interacting ligands. Biochemistry 40, 15194–15202 (2001)

    Article  CAS  Google Scholar 

  16. Smith, F. W., Schultze, P. & Feigon, J. Solution structures of unimolecular quadruplexes formed by oligonucleotides containing Oxytricha telomere repeats. Structure 3, 997–1008 (1995)

    Article  CAS  Google Scholar 

  17. Balagurumoorthy, P. B. & Brahmachari, S. K. Structure and stability of human telomeric sequence. J. Biol. Chem. 269, 21858–21869 (1994)

    CAS  Google Scholar 

  18. Read, M. A. et al. Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: Structure–activity relationships. J. Med. Chem. 42, 4538–4546 (1999)

    Article  CAS  Google Scholar 

  19. Harrison, R. J., Gowan, S. M., Kelland, L. R. & Neidle, S. Human telomerase inhibition by substituted acridine derivatives. Bioorg. Med. Chem. Lett. 9, 2463–2468 (1999)

    Article  CAS  Google Scholar 

  20. Han, H., Langley, D. R., Rangan, A. & Hurley, L. H. Selective interactions of cationic porphyrins with G-quadruplex structures. J. Am. Chem. Soc. 123, 8902–8913 (2001)

    Article  CAS  Google Scholar 

  21. Riou, J. F. et al. Cell senescence and telomere shortening induced by a new series of specific G-quadruplex DNA ligands. Proc. Natl Acad. Sci. USA 99, 2672–2677 (2002)

    Article  ADS  CAS  Google Scholar 

  22. Koeppel, F. et al. Ethidium derivatives bind to G-quartets, inhibit telomerase and act as fluorescent probes for quadruplexes. Nucleic Acids Res. 29, 1087–1096 (2001)

    Article  CAS  Google Scholar 

  23. Fedoroff, O. Y. et al. NMR-based model of a telomerase-inhibiting compound bound to G-quadruplex DNA. Biochemistry 37, 12367–12374 (1998)

    Article  CAS  Google Scholar 

  24. Read, M. A. & Neidle, S. Structural characterization of a guanine–quadruplex ligand complex. Biochemistry 39, 13422–13432 (2000)

    Article  CAS  Google Scholar 

  25. Han, H., Cliff, C. L. & Hurley, L. H. Accelerated assembly of G-quadruplex structures by a small molecule. Biochemistry 38, 6981–6986 (1999)

    Article  CAS  Google Scholar 

  26. Otwinowski, Z. M. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307–326 (1997)

    Article  CAS  Google Scholar 

  27. Brünger, A. T. et al. Crystallography & NMR system: A new software suite for macromolecular structure determination. Acta. Crystallogr. D 54, 905–921 (1998)

    Article  Google Scholar 

  28. Sheldrick, G. M. & Schneider, T. R. SHELX-97: high-resolution refinement. Methods Enzymol. 276, 319–343 (1997)

    Article  Google Scholar 

  29. Cambilleau, C. & Horjales, E. TOM:A FRODO subpackage for protein-ligand fitting with interactive energy minimisation. J. Mol. Graphics 5, 175–177 (1987)

    Google Scholar 

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Acknowledgements

We are grateful to Cancer Research UK for support of these studies, and various colleagues for discussions, especially M. Read, J. Harrison, G. Chessari and L. Pearl. We thank M. Roe and the ID14 beamline staff for assistance with data collection.

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Authors and Affiliations

  1. The Cancer Research UK Biomolecular Structure Unit, Chester Beatty Laboratories, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB, London, UK

    Gary N. Parkinson, Michael P. H. Lee & Stephen Neidle

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  1. Gary N. Parkinson
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Correspondence to Stephen Neidle.

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Parkinson, G., Lee, M. & Neidle, S. Crystal structure of parallel quadruplexes from human telomeric DNA. Nature 417, 876–880 (2002). https://doi.org/10.1038/nature755

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