A new structure formed by a DNA sequence that is known to be important in cancer development is reported in the August issue of Nature Chemical Biology. This structural information should help scientists develop a new range of anticancer drugs.
Human c-Myc is a transcription factor that is central to regulation of cell proliferation. The MYC gene in normal cells is tightly regulated and is only expressed when cells actively divide. In contrast, cancer cells may express the gene in an uncontrolled fashion. One particular region of MYC DNA, which controls up to 90% of its transcription, is composed of a purine-rich strand that adopts other biologically relevant structures beyond the Watson-Crick double helix. One such DNA structure, the G-quadruplex, is formed by the stacking of guanine tetrads, comprising four guanines arranged in a flat ring. Stabilization of G-quadruplex structures, by small-molecule ligands is known to decrease MYC expression levels.
Patel and coworkers used nuclear magnetic resonance spectroscopy to characterize an entirely new G-quadruplex structure of a five-guanine-tract MYC DNA sequence, in contrast to previous structures containing four-guanine-tract sequences. They also showed the structure of this new five-guanine-tract sequence in complex with a small-molecule porphyrin, which is known to stabilize G-quadruplex structures.
The authors suggest that the structural information derived from this and other small-molecule interactions with G-quadruplex structures will provide a platform for the development of a new class of anticancer compounds that target G-quadruplex DNA structures.
Dinshaw J. Patel (Memorial Sloan-Kettering Cancer Center, New York, NY, USA)
Anh Tuan Phan (Memorial Sloan-Kettering Cancer Center, New York, NY, USA)
Also published online.
(C) Nature Chemical Biology press release.
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