A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III 1
AffiliationUniversity of Arizona Cancer Center
University of Arizona, College of Pharmacy
MetadataShow full item record
PublisherAMER CHEMICAL SOC
CitationA Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III 1 2016, 138 (42):14138 Journal of the American Chemical Society
Rights© 2016 American Chemical Society
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AbstractMYC is overexpressed in many different cancer types and is an intensively studied oncogene because of its contributions to tumorigenesis. The regulation of MYC is complex, and the NHE III1 and FUSE elements rely upon noncanonical DNA structures and transcriptionally induced negative superhelicity. In the NHE III1 only the G-quadruplex has been extensively studied, whereas the role of the i-motif, formed on the opposite C-rich strand, is much less understood. We demonstrate here that the i-motif is formed within the 4CT element and is recognized by hnRNP K, which leads to a low level of transcription activation. For maximal hnRNP K transcription activation, two additional cytosine runs, located seven bases downstream of the i-motif-forming region, are also required. To access these additional runs of cytosine, increased negative superhelicity is necessary, which leads to a thermodynamically stable complex between hnRNP K and the unfolded i-motif. We also demonstrate mutual exclusivity between the MYC G-quadruplex and i-motif, providing a rationale for a molecular switch mechanism driven by SP1-induced negative superhelicity, where relative hnRNP K and nucleolin expression shifts the equilibrium to the on or off state.
Note12 month embargo. First available online 26 September 2016.
VersionFinal accepted manuscript
SponsorsNational Science Foundation [CH-1609514, CHE-1415883]; National Institutes of Health [5R01CA153821, 1R01GM085585]; National Foundation for Cancer Research [VONHOFF-15-01]