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 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.
College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
Adam
A
Siddiqui-Jain
Cory L
CL
Grand
David J
DJ
Bearss
Laurence H
LH
Hurley
D001483:Base Sequence; D004247:DNA; D016259:Genes, myc; D006367:HeLa Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
D012097:Repressor Proteins; D004247:DNA