Direct Evidence for a G-Quadruplex in a Promoter Region
and Its Targeting with a Small Molecule To Repress c-MYC Transcription

The nuclease hypersensitivity element III1 upstream of the P1 promoter of c-MYC controls 85-90% of the transcriptional activation of this gene. We have demonstrated that the purine-rich strand of the DNA in this region can form two different intramolecular G-quadruplex structures, only one of which appears to be biologically relevant. This biologically relevant structure is the kinetically favored chair-form G-quadruplex, which when mutated with a single G to A transition is destabilized, resulting in a 3-fold increase in basal transcriptional activity of the c-MYC promoter. The cationic porphyrin TMPyP4, which has been shown to stabilize this G-quadruplex structure, is able to further suppress c-MYC transcriptional activation. These results provide compelling evidence that a specific G-quadruplex structure formed in the c-MYC promoter region functions as a transcriptional repressor element. Furthermore, we establish the principle that c-MYC transcription can be controlled by ligand-mediated G-quadruplex stabilization. QUADRUPLEX SEEN IN HUMAN CELLS Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c- MYCtranscription

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All contents copyright © 2002. Laurence H. Hurley, Ph.D.

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