The Consequences of Overlapping G-Quadruplexes and i-Motifs in the Platelet-Derived Growth Factor Receptor β Core Promoter Nuclease Hypersensitive Element Can Explain the Unexpected Effects of Mutations and Provide Opportunities for Selective Targeting of Both Structures by Small Molecules To Downregulate Gene Expression

• DOI: 10.1021/jacs.6b10028
• Publication Date: 2017-05-04T18:55:51Z
• Authors: Robert V. Brown; Ting Wang; Venkateshwar Redd...; Guanhui Wu; Buket Onel; Reena Chawla; Hector Quijada; Sara M. Camp; Eddie T. Chiang; Quinea R. Lassiter; Carmen Lee; Shivani Phanse; Megan A. Turnidge; Ping Zhao; Joe G. N. Garcia; Vijay Gokhale; Danzhou Yang; Laurence H. Hurley
• Keywords: G-quadruplex; Nuclease

The platelet-derived growth factor receptor β (PDGFR-β) signaling pathway is a validated and important target for the treatment of certain malignant nonmalignant pathologies. We previously identified G-quadruplex-forming nuclease hypersensitive element (NHE) in human PDGFR-β promoter that putatively forms four overlapping G-quadruplexes. Therefore, we further investigated structures biological roles G-quadruplexes i-motifs NHE with ultimate goal demonstrating an alternate effective strategy molecularly targeting pathway. Significantly, show primary G-quadruplex repression 3'-end G-quadruplex, which has GGA sequence at 3'-end. Mutation studies using luciferase reporter plasmids highlight novel set point mutations, some seem to provide conflicting results on effects gene expression, prompting investigation into effect these mutations i-motif-forming strand. Herein characterize formation equilibrium between least two different from cytosine-rich (C-rich) NHE. apparently mutation can be rationalized if take account single base made critical cytosine run dramatically affects formed this sequence. group ellipticines targets promoter, series compounds, selected ellipticine analog GSA1129, selectively shift dynamic full-length favor structure. also benzothiophene-2-carboxamide (NSC309874) as i-motif-interactive compound. In vitro, GSA1129 NSC309874 downregulate activity transcript neuroblastoma cell line SK-N-SH subcytotoxic concentrations. inhibits PDGFR-β-driven proliferation migration. With established preclinical murine model acute lung injury, demonstrate attenuates endotoxin-mediated inflammation. Our underscore importance considering structure G- C-rich sequences evidence involvement both strands associated control expression.