Nucleic acid clamp-mediated recognition and stabilization of the physiologically relevant MYC promoter G-quadruplex.
Nucleic Acids Res
; 44(22): 11013-11023, 2016 12 15.
Article
en En
| MEDLINE
| ID: mdl-27789698
ABSTRACT
The MYC proto-oncogene is upregulated, often at the transcriptional level, in â¼80% 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 (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 (G42-5 and 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oligonucleótidos
/
Proteínas Proto-Oncogénicas c-myc
/
Regiones Promotoras Genéticas
/
G-Cuádruplex
Límite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos