title: A small molecule that disrupts G-quadruplex DNA structure and enhances gene expression.
abstract: It has been hypothesized that the formation of G-quadruplex structures in the DNA of gene promoters may be functionally linked to transcription and consequently that small molecules that interact with such G-quadruplexes may modulate transcription. We previously reported that triarylpyridines are a class of small molecules that selectively interact with G-quadruplex DNA. Here we describe an unexpected property of one such ligand that was found to disrupt the structure of two different DNA G-quadruplex structures, each derived from sequence motifs in the promoter of the proto-oncogene c-kit. Furthermore, cell-based experiments in a cell line that expresses c-kit (HGC-27) showed that the same ligand increased the expression of c-kit. This contrasts with G-quadruplex-inducing ligands that have been previously found to inhibit gene expression. It would thus appear that the functional consequence of small molecule ligands interacting with G-quadruplex structures may depend on the specific mode of interaction. These observations provide further evidence to suggest that G-quadruplex forming sequence motifs play a role that relates to transcription.
authors.affiliation: The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Zoë A E
authors.initials: ZA
authors.lastname: Waller
authors.forename: Sven A
authors.initials: SA
authors.lastname: Sewitz
authors.forename: Shang-Te Danny
authors.initials: ST
authors.lastname: Hsu
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
mesh_terms: D000042:Absorption; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011725:Pyridines; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit
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