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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-09, Vol.99 (18), p.11593-11598
• Main Authors: Siddiqui-Jain, Adam, Grand, Cory L., Bearss, David J., Hurley, Laurence H.
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological Sciences; Cancer; DNA; Genes; Genes, myc; HeLa Cells; Humans; Mutagenesis, Site-Directed; Mutation; Promoter Regions, Genetic; Repressor Proteins - metabolism; Transcription, Genetic - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.182256799

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.