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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2009 May 14; Vol. 52 (9), pp. 2863-74. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Base Composition
Base Sequence
Bromine pharmacology
DNA, Single-Stranded chemistry
DNA, Single-Stranded metabolism
DNA, Superhelical metabolism
Deoxyribonuclease I metabolism
Humans
Mutation drug effects
Nucleic Acid Denaturation
Potassium Chloride pharmacology
Potassium Permanganate pharmacology
Single-Strand Specific DNA and RNA Endonucleases genetics
Single-Strand Specific DNA and RNA Endonucleases metabolism
Sphingosine analogs & derivatives
Sphingosine pharmacology
Transcription, Genetic
DNA, Superhelical chemistry
Drug Design
G-Quadruplexes drug effects
Gene Expression Regulation
Genes, myc genetics
Nucleic Acid Conformation
Promoter Regions, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 52
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19385599
- Full Text :
- https://doi.org/10.1021/jm900055s