A Small Molecule That Disrupts G-Quadruplex DNA Structure and Enhances Gene Expression

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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.