The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression.
The importance of DNA supercoiling in transcriptional regulation has been known for many years, and more recently, transcription itself has been shown to be a source of this superhelicity. To mimic the effect of transcriptionally induced negative superhelicity, the G-quadruplex/i-motif-forming region in the c-Myc promoter was incorporated into a supercoiled plasmid. We show, using enzymatic and chemical footprinting, that negative superhelicity facilitates the formation of secondary DNA structures under physiological conditions. Significantly, these structures are not the same as those formed in single-stranded DNA templates. Together with the recently demonstrated role of transcriptionally induced superhelicity in maintaining a mechanosensor mechanism for controlling the firing rate of the c-Myc promoter, we provide a more complete picture of how c-Myc transcription is likely controlled. Last, these physiologically relevant G-quadruplex and i-motif structures, along with the mechanosensor mechanism for control of gene expression, are proposed as novel mechanisms for small molecule targeting of transcriptional control of c-Myc.
Sun
Daekyu
D
College of Pharmacy, University of Arizona, Tucson, Arizona 85721, USA. sun@pharmacy.arizona.edu
Hurley
Laurence H
LH
D001482:Base Composition; D001483:Base Sequence; D001966:Bromine / Q000494:pharmacology; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry* / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects*; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000187:drug effects; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D011189:Potassium Chloride / Q000494:pharmacology; D011196:Potassium Permanganate / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic
D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D011196:Potassium Permanganate; D011189:Potassium Chloride; D003850:Deoxyribonuclease I; D015719:Single-Strand Specific DNA and RNA Endonucleases; C061800:N,N-dimethylsphingosine; D013110:Sphingosine; D001966:Bromine