Breakthrough improves understanding of drug-DNA interactions

A new tool that can show how small molecules interact with the genome has been developed by scientists in Cambridge, which holds promise in the development of novel cancer therapeutics.

The tool, called Chem-map, uses already existing genomic sequencing technology to map the interactions between the molecular structure of cancer drugs and chromatin, which is the structure in the nucleus of the cell where DNA is wrapped around spherical proteins.

'When a therapeutic drug enters a cancer cell with a genome that has three billion bases, it's like entering a black box,' said co-first author Dr Zutao Yu from the University of Cambridge. 'Understanding how drugs work in the body is essential to creating better, more effective therapies.'

Many cancer drugs, such as doxorubicin, are small molecules that interact with cellular DNA. However, how the drugs interact with the genome is not well understood.

In a leukaemia cell line, the researchers were able to determine the direct binding sites of doxorubicin using Chem-map. They achieved this by using two antibodies as a scaffold for a DNA-cutting complex, called a transposon. The transposons cut the DNA on either side of the binding site, leaving a spliced fragment of DNA bound to doxorubicin. The fragment can then be sequenced and mapped to an existing library of the human genome, resulting in a map with information about where doxorubicin interacts with DNA.

Clinical trials are currently ongoing to investigate the combination therapy of doxorubicin with another drug, tucidinostat.

Here, the researchers have shown, using Chem-map, that doxorubicin binding changes in cells that have been subjected to tucidinostat. The results show that the epigenetic changes caused by tucidinostat can enhance the interaction between doxorubicin and the genome, resulting in the potential use of lower doses of the drugs, reducing adverse reactions.

'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,' said Professor Sir Shankar Balasubramanian, the lead researcher of the project, who previously won the Millennium Technology Prize for his part in developing next-generation DNA sequencing (see BioNews 1096). '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.'

The authors also expect that Chem-map can be adapted to a wide range of DNA-interacting therapeutics, not limiting its application to cancer research.