Cancer is initiated by genetic instability, a "hallmark" of cancer. The sites where cancer-causing instabilities occur are not random but are localized to genomic "hotspots" often comprised of sequences that can form alternative or "non-B" DNA structures (e.g., H-DNA). We found that these sequences are enriched at mutation hotspots in human cancer genomes in many cancer types and cause mutations in mammals, implicating them in cancer etiology. However, the mechanisms are still unclear, in part due to the lack of chemical probes to detect and/or regulate the formation of mutagenic non-B DNA in vivo and the limited platforms to identify and develop these tools. Thus, our g...

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Cancer is initiated by genetic instability, a "hallmark" of cancer. The sites where cancer-causing instabilities occur are not random but are localized to genomic "hotspots" often comprised of sequences that can form alternative or "non-B" DNA structures (e.g., H-DNA). We found that these sequences are enriched at mutation hotspots in human cancer genomes in many cancer types and cause mutations in mammals, implicating them in cancer etiology. However, the mechanisms are still unclear, in part due to the lack of chemical probes to detect and/or regulate the formation of mutagenic non-B DNA in vivo and the limited platforms to identify and develop these tools. Thus, our goal is to address this gap by identifying these tool compounds through the use of our novel H-FRET assay, a high throughput screening platform that can detect both H-DNA-stabilizing and -destabilizing compounds. We will then test the identified compounds for their ability to modulate H-DNA-induced genetic instability in human cancer cells. Our long-term goal is to use these compounds to guide the development of novel strategies to prevent and/or treat cancer. The potential significance of the results is multi-faceted. Technologically, we will address the need for a facile, high throughput approach to identify DNA structure-selective compounds. Mechanistically, we can use the compounds to interrogate DNA structure and function in human cells and to potentially visualize and manipulate DNA structure and function in living organisms. Translationally, the identified ligands can serve as leads for novel therapeutic strategies for the treatment/prevention of cancer, thereby benefitting cancer patients. We expect that the results obtained will impact cancer research by contributing fundamental new knowledge to accelerate further research in the areas of genetic instability, cancer biology, and novel therapeutics for the prevention/treatment of cancer.

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