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FOLDED DNA
Four-stranded forms of DNA called G-quadruplexes are believed to play important functional roles in living cells--such as in telomeres, the protein-DNA assemblies found at the ends of chromosomes. But until now, no one had verified that G-quadruplex structures actually exist in human cells, although they'd been found in protozoa.
The work was carried out by postdoc Adam Siddiqui-Jain, grad student Cory L. Grand, assistant professor of molecular and cellular biology David J. Bearss, and professor of medicinal chemistry Laurence H. Hurley [Proc. Natl. Acad. Sci. USA, published online Aug. 23, http://www.pnas.org/cgi/doi/10.1073/pnas.182256799]. The study "suggests not only that a G-quadruplex structure does form within chromosomal DNA, but that it can also be a target for selective small molecules," comments associate professor of pharmacology and biochemistry David R. Corey of the University of Texas Southwestern Medical Center, Dallas. "This exciting finding opens up a new strategy for gene regulation and reminds us that DNA in cells is not a featureless desert devoid of interesting topology." Hurley's group finds that a cationic porphyrin compound--tetra(N-methyl-4-pyridyl)porphine (TMPyP4)--recognizes and binds specifically to a 20- to 30-base region of folded DNA in c-Myc and inhibits expression of the gene. This is reminiscent of the way small-molecule drugs recognize and inhibit specific proteins, suggesting that quadruplex-targeted compounds might be useful therapeutically. For example, assistant professor of medicine Dean W. Felsher of Stanford University and coworkers recently reported that brief inactivation of Myc expression causes tumor shrinkage and conversion of bone-cancer cells into normal bone-generating cells [Science, 297, 102 (2002)]. "The external control of oncogene expression is arguably one of the most important goals in cancer research," Hurley tells C&EN. "The occurrence of a G-quadruplex in the c-Myc promoter does not appear to be an isolated case, but is rather a general phenomenon in many genes involved in proliferative signaling. In continuing studies, we have demonstrated G-quadruplex formation and probable involvement in the regulation of a number of other oncogenes and growth factors. Thus, we believe this paper opens the door to a whole new field of research, not to mention a new class of cancer therapeutics." The first quadruplex structure in vivo--in ciliate cells--was reported by biochemistry professor Andreas Plückthun of the University of Zurich and coworkers [Proc. Natl. Acad. Sci. USA, 98, 8572 (2001)]. And a group led by Tomas Simonsson, now at Cambridge University's Laboratory of Molecular Biology, first proposed that a G-quadruplex might control c-Myc gene expression [Nucleic Acids Res., 26, 1167 (1998)]. Cyternex, a San Diego biotech firm founded by Hurley, is developing quadruplex-targeted drugs based on the new findings.
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