title: 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 III1region. Under a variety of conditions, multiple isoforms have been described to form from the first four continuous guanine runs (G41-4) 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 (G41-4) over the other major structures (G42-5and G41-5, 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.
authors: BioMolecular Sciences, University of Mississippi, University, MS 38677, USA.
authors: Taisen
authors: T
authors: Hao
authors: Pharmacy, Charleston Area Medical Center Memorial Hospital, Charleston, WV 25304, USA.
authors: Vanessa C
authors: VC
authors: Gaerig
authors: BioMolecular Sciences, University of Mississippi, University, MS 38677, USA tabrooks@olemiss.edu.
authors: Tracy A
authors: TA
authors: Brooks
mesh_terms: D001483:Base Sequence; D054856:G-Quadruplexes; D015870:Gene Expression; D020868:Gene Silencing; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D009841:Oligonucleotides / Q000737:chemistry* / Q000235:genetics; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; C489427:MYC protein, human; D009841:Oligonucleotides; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D049409:Luciferases, Firefly