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‘Knots’ in DNA a Focus of Future Cancer Therapy

‘Knots’ in DNA a Focus of Future Cancer Therapy

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.

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