Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c- <i>MYC</i> transcription

The nuclease hypersensitivity element III 1 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 seems to be biologically relevant. This biologically relevant structure is the kinetically favored chair-form G-quadruplex, which is destabilized when mutated with a single G → A transition, 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 suppress further 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.