Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length
AffiliationUniv Arizona, Coll Sci, Dept Chem & Biochem
MetadataShow full item record
PublisherAMER CHEMICAL SOC
CitationACS Omega 2019, 4, 2533−2539
Rights© 2019 American Chemical Society
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractThe important MYC oncogene is deregulated in many cancer cells and comprises one of the most prominent G-quadruplex (G4) forming sequences in its promoter regions, the NHE III1 motif. Formation of G4s suppresses MYC transcription and can be modulated by drug binding, establishing these DNA structures as promising targets in cancer therapy. The NHE III1 motif can fold into more than one parallel G4s, including 1:2:1 and 1:6:1 loop length conformers, with the 1:2:1 conformer shown as the major species under physiological conditions in solution. However, additional factors such as protein interactions may affect the cellular folding equilibrium. Nucleolin, a protein shown to bind MYC G4 and repress MYC transcription, is reported herein to preferably bind to the 1:6:1 loop length conformer suggesting a physiological significance of this species. The high-resolution NMR solution structure of the 1:6:1 conformer is determined, which reveals a 5'-capping structure distinctive from the 1:2:1 form, with the 6 nt central loop playing an essential role for this specific capping structure. This suggests that each parallel G-quadruplex likely adopts unique capping and loop structures determined by the specific central loop and flanking sequences. The resulting structural information at the molecular level will help to understand protein recognition of different G4s, contribution of G4 polymorphism to gene regulation, and to rationally design small molecules selectively targeting the 1:6:1 MYC G4.
NoteOpen access journal
VersionFinal published version
SponsorsNational Institutes of Health [R01CA177585, P30CA023168]