SCIENCE & TECHNOLOGY
QUADRUPLEX IN ITS ELEMENT Structures of human telomeric quadruplex in cell-like solution have implications for anticancer therapeutics STU BORMANp C&EN WASHINGTON
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versity of Arizona and coworkers, by N M R {Nucleic Acids Res. 2006,34,2723); and Patel, senior research scientist Anh Tuan Phan, and coworkers, also by N M R (J. Am. Chem. Soc, DOI: 10.1021/ja062791w). The overall folding pattern revealed in the three models is a novel one that had not been seen before in human telomeric quadruplexes. In theJ^GS paper, Patel's group also reports having obtained a more detailed 3-D K+-solution structure of the quadruplex by making minor substitutions in the human telomeric D N A sequence, rendering the structure NMR-interpretable for the first time. In a yet-to-be-published study, Yang and coworkers have also determined a 3-D N M R structure of another slightly modified telomere sequence in K+ solution. Although structures of unmodified native sequences would have been : more desirable, the new strucI tures provide about as close an approximation to the fully human structure as can currently be achieved. Different quadruplex structures are believed to be I in equilibrium at telomere ends, so the structures obtained so far are probably not the "end" of the § story in any case. "Our future efforts will be directed toward deciphering the folding topologies of other quadruplex conformations that are formed by human telomere sequences in K+ solution," note Patel, Phan, and coworkers in their paper.
IKE THE AGLETS AT THE END lution has been especially sought, because a of your shoelaces, protein-andcrystal structure may not always accurately D N A assemblies known as reflect the conformations that molecules telomeres protect the ends of adopt in living cells. The structure of the your chromosomes from fraying. human quadruplex in K+ solution, however, In work with potential implications for has resisted analysis. the development of anticancer therapeutics, the folding pattern of DNA quadruplexes formed by human telomeres in a medium closely resembling the cellular environment now has been found by three groups. Two of the groups have also succeeded in obtaining the first three-dimensional solution structures of a human telomeric quadruplex in the same cell-like media. The single-stranded telomere terminus can adopt the shape of a quadruplex, a folded conformation formed by some guaninerich D N A repeat sequences. The 3-D structure adopted by human telomeric quadruplexes THE NEW N M R solution strucis of particular interest for antitures share some features with cancer drug discovery efforts, the Na + -solution and K + -conas drugs are being designed to taining-crystal structures deterinteract with such structures mined earlier, but they also differ to inhibit telomere extension, a from them substantially in key process that occurs selectively ways. Researchers will no doubt in cancer cells. be carefully stadying the features Various groups have obtained TRIPLE QUAD The Patel group's structure of the human of these structures as targets for 3-D human telomeric quadru- telomeric quadruplex in K+ solution (top left) shares some plex structures. For example, features with two earlier structures (in Na+ solution, middle anticancer drug discovery. + The work is a major step tostructural biologist Dinshaw J. left, and in a K -containing crystal, bottom left) and yet is ward the goal of better underPatel of Memorial Sloan-Ketter- distinctly different from each. Corresponding topologies of standing the structure of human ing Cancer Center and cowork- each of the three structures are also shown (right); loops telomeres. The three groups ers obtained the nuclear mag- are red, and the rest of the DNA strands are black lines "concur in finding an important netic resonance spectroscopy with arrows. Guanines are blue and purple, and sugar-ring new category of fold for this structure of human telomeric oxygens are yellow. structure, with two lateral loops quadruplexes in Na+-containing and one propeller loop, although it is not Now three groups have determined the solution in 1993. And a group led by profesclear to what extent it is the dominant spefolding pattern, or topology, of the human sor Stephen Neidle of the School of Pharcies in solution," Neidle comments. "There telomeric quadruplex: chemistry professor macy at the University of London obtained is still much to learn about these complex Hiroshi Sugiyama and coworkers at Kyoto X-ray structures of human quadruplexes in + molecules, and we all agree that more highUniversity, in Japan, by circular dichroism a K -containing crystal in 2002. spectroscopy (Bioorg. Med. Chem. 2006,14, resolution structure analyses will continue K+ solution is considered more biologito be important as the best way of obtaining 5584); assistant professor of pharmacology cally relevant than Na+ solution because K+ topological information." • and toxicology Danzhou Yang of the Unipredominates in cells. A structure in K+ so-
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