NEW ORLEANS"Knots" in DNA may become potential targets of cancer therapeutics, according to an investigator who described these new structures at the 92nd Annual Meeting of the American Association for Cancer Research (AACR abstract 1123).
These so-called knots occur when DNA folds over upon itself, creating a variety of complex three-dimensional, four-stranded structures called quadruplexes.
Some of these knot-like structures have been linked to known oncogenes and cancer-triggering processes, and may possess active sites that could serve as targets for new cancer therapeutics, said Laurence H. Hurley, PhD, DSc, the Howard J. Schaeffer Chair in Pharmaceutical Sciences at the University of Arizona Health Sciences Center, Tucson.
"We are looking at the role of higher order DNA structures in regulating certain genes," Dr. Hurley said. "Specifically, we’re investigating the role a quadruplex plays in the regulatory region of c-myc, a known oncogene. The unregulated expression of c-myc is a causal event in the formation of many tumors and leads to activation of other important factors, such as telomerase."
In describing how quadruplexes work, Dr. Hurley noted that DNA sequence information is pivotal to transcription, replication, and recombination of molecules, and that DNA structure is dependent on certain intracellular conditions that may facilitate the stabilization of specific secondary structures.
Dependent on the primary DNA sequence, purine-rich strands of DNA can adopt quadruplexes, Dr. Hurley said. These quadruplexes appear to exist in biologically important regions of DNA such as the ends of chromosomes (telomeres), and in the regulatory regions of oncogenes like c-myc.
"Our research has focused on developing compounds that help this quadruplex to form, then bind to it and stabilize it, thereby turning off the c-myc gene," he said. Certain proteins, such as topoisomerase I, facilitate the formation of quadruplexes, he said.