DNA Sequencing Method Detects Drug-Genome Interactions

Scientists at the University of Cambridge have developed a new DNA sequencing method to detect where and how small molecule drugs interact with the targeted genome. The new method, called Chem-map, allows researchers to conduct in situ mapping of small molecule-genome interactions with unprecedented precision using a strategy called small-molecule-directed transposase Tn5 tagmentation. This detects the binding site in the genome where a small molecule binds to genomic DNA or DNA-associated proteins.

Millions of cancer patients have received treatment with genome-targeting drugs, such as doxorubicin. But despite decades of clinical use and research, the molecular mode of action with the genome is still not well-understood. 

"Understanding how drugs work in the body is essential to creating better, more effective therapies," explains co-first author Dr. Zutao Yu from the Yusuf Hamied Department of Chemistry. "But when a therapeutic drug enters a cancer cell with a genome that has three billion bases, it's like entering a black box."

The powerful method, called Chem-map, lifts the veil of this genomic black box by enabling researchers to detect where small molecule drugs interact with their targets on the DNA genome. This information can help researchers to develop better drugs in the future by understanding how various medications interact with the genome, allowing them to create more specific therapies targeting cancer cells. 

In the study, the researchers used Chem-map to determine the direct binding sites of the widely used anticancer drug doxorubicin in human leukemia cells. The technique also showed how the combined therapy of doxorubicin on cells already exposed to the histone deacetylase (HDAC) inhibitor tucidinostat could have a potential clinical advantage. This could lead to the development of new treatment protocols that combine different drugs to target cancer cells more effectively.

Chem-map also has the potential to be used for mapping other molecules on DNA G-quadruplexes, known as G4s. G4s are four-stranded secondary structures that have been implicated in gene regulation, and could be possible targets for future anti-cancer treatments. In situ mapping with Chem-map of small-molecule interactions with DNA and chromatin proteins provides insights that will enhance understanding of genome and chromatin function and therapeutic interventions.

Senior author Professor Sir Shankar Balasubramanian says, "Chem-map is a powerful new method to detect the site in the genome where a small molecule binds to DNA or DNA-associated proteins. It provides enormous insights on how some drug therapies interact with the human genome, and makes it easier to develop more effective and safer drug therapies."