Nucleic acid clamp-mediated recognition and stabilization of the physiologically relevant MYC promoter G-quadruplex

Abstract

The MYC proto-oncogene is upregulated, often at the transcriptional level, in ∼80% of all cancers. MYC's promoter is governed by a higher order G-quadruplex (G4) structure in the NHE III₁ region. Under a variety of conditions, multiple isoforms have been described to form from the first four continuous guanine runs (G4_1-4) predominating under the physiologically relevant supercoiled conditions. In the current study, short oligonucleotides complementing the 5'- and 3'-regions flanking the G4 have been connected by an abasic linker to form G4 clamps, varying both linker length and G4 isoform being targeted. Clamp A with an 18 Å linker was found to have marked affinity for its target isomer (G4_1-4) over the other major structures (G4_2-5 and G4_1-5, recognized by clamps B and C, respectively), and to be able to shift equilibrating DNA to foster greater G4 formation. In addition, clamp A, but not B or C, is able to modulate MYC promoter activity with a significant and dose-dependent effect on transcription driven by the Del4 plasmid. This linked clamp-mediated approach to G4 recognition represents a novel therapeutic mechanism with specificity for an individual promoter structure, amenable to a large array of promoters.