Modulation of DNA structure formation using small molecules

Genome integrity is essential for proper cell function such that genetic instability can result in cellular dysfunction and disease. Mutations in the human genome are not random, and occur more frequently at "hotspot" regions that often co-localize with sequences that have the capacity to adopt alternative (i.e. non-B) DNA structures. Non-B DNA-forming sequences are mutagenic, can stimulate the formation of DNA double-strand breaks, and are highly enriched at mutation hotspots in human cancer genomes. Thus, small molecules that can modulate the conformations of these structure-forming sequences may prove beneficial in the prevention and/or treatment of genetic diseases. Further, the development of molecular probes to interrogate the roles of non-B DNA structures in modulating DNA function, such as genetic instability in cancer etiology are warranted. Here, we discuss reported non-B DNA stabilizers, destabilizers, and probes, recent assays to identify ligands, and the potential biological applications of these DNA structure-modulating molecules.