Cambridge father of DNA sequencing excited by potential of Chem-map to understand how drugs interact with human genome

One of the fathers of modern DNA sequencing has led research into a powerful new method of understanding how many drugs interact with the human genome.

Professor Sir Shankar Balasubramanian, of the University of Cambridge, says Chem-map will make it easier to develop new therapies.

Dr Shankar Balasubramanian. Picture: Nathan Pitt / University of Cambridge
Dr Shankar Balasubramanian. Picture: Nathan Pitt / University of Cambridge

It lifts the lid on the genomic black box by enabling researchers to detect where small molecule drugs interact with their targets on the DNA genome.

Many drugs directly interact with our DNA to treat diseases such as cancer. But even though millions of people are treated with them every year, the molecular mode of action within the genome has remained poorly understood.

“Understanding how drugs work in the body is essential to creating better, more effective therapies. But when a therapeutic drug enters a cancer cell with a genome that has three billion bases, it’s like entering a black boxl,” said Dr Zutao Yu, from the Yusuf Hamied Department of Chemistry, co-first author of the new paper published in the journal Nature Biotechnology.

“I am so proud that we have been able to solve this longstanding problem – we have established a highly efficient approach which will open many paths for new research.”

Chem-map allows researchers to conduct in situ mapping of small molecule-genome interactions with unprecedented precision, thanks to an approach known as small-molecule-directed transposase Tn5 tagmentation.

It detects the site in the genome where a small molecule binds to genomic DNA or DNA-associated proteins.

“Lots of life-saving drugs directly interact with DNA to treat diseases such as cancer,” said co-first author Dr Jochen Spiegel. “Our new method can precisely map where drugs bind to the genome, which will help us to develop better drugs in the future.”

The researchers used Chem-map to determine the direct binding sites in human leukaemia cells of the commonly used anti-cancer drug doxorubicin.

They showed how the combined therapy of using doxorubicin on cells already exposed to the histone deacetylase (HDAC) inhibitor tucidinostat could have a potential clinical advantage.

And they used the technique to map the binding sites of molecules on DNA G-quadruplexes, known as G4s. These four-stranded secondary structures are implicated in gene regulation, meaning they could be future targets for cancer therapies.

Prof Balasubramanian, renowned for devising groundbreaking DNA sequencing technology in 1997 with Dr David Klenerman, said: “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.”

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