A Mechanosensor Mechanism Controls the G-Quadruplex/i-Motif Molecular Switch in the MYC Promoter NHE III1.
MYC 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 III1and FUSE elements rely upon noncanonical DNA structures and transcriptionally induced negative superhelicity. In the NHE III1only 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.
University of Arizona Cancer Center , 1515 North Campbell Avenue, Tucson, Arizona 85724, United States.
Caleb
C
Sutherland
Department of Chemistry and Biochemistry and School of Biomedical Sciences, Kent State University , Kent, Ohio 44242, United States.
Yunxi
Y
Cui
Department of Chemistry and Biochemistry and School of Biomedical Sciences, Kent State University , Kent, Ohio 44242, United States.
Hanbin
H
Mao
University of Arizona Cancer Center , 1515 North Campbell Avenue, Tucson, Arizona 85724, United States.|University of Arizona , College of Pharmacy, 1703 East Mabel Street, Tucson, Arizona 85721, United States.|BIO5 Institute , 1657 East Helen Street, Tucson, Arizona 85721, United States.
Laurence H
LH
Hurley