DNA ‘switch’ found in fight against cancer

Scientists from the University of Bradford have discovered a DNA protein ‘switch’ that could help in the treatment of cancer and dementia.

The findings, published this week in the prestigious journal Nature Communications, were described by the lead author Prof Sherif El-Khamisy as “significant”.

They involve the identification of a mechanism that regulates the creation of something called R-loops, which are part of our DNA. R-loops are very ‘brittle’ and prone to breaking. Too many R-loops can lead to cell death, whereas not enough causes disruption of protein production.

Now for the first time, a process by which R-loops are regulated in our DNA has been identified. The work follows five years of research.

Prof El-Khamisy said: “It is significant because it has not been clear until now how those structures are regulated in our cells. Also by identifying these proteins that regulate R-loops and the link between them, we can design drugs to manipulate the process in the way we want. We are getting one step closer to finding drugs that can modify the progression of some diseases including cancer, dementia and conditions which affect co-ordination, like ataxia and Huntington’s Disease, which are associated with perturbed R-loops.”

What are R-loops?

R-loops form naturally during DNA metabolism and are used to regulate the production of various proteins in the body. However, they can have both positive and negative effects, depending on their frequency and location. Too many R-loops can lead to DNA instability and cell death. Too few means the body cannot make the proteins it needs.

The three proteins which regulate R-loops are called senataxin, USP11 and KEAP1.

What do the findings mean?

The lead author, Prof El-Khamisy said they had now discovered a mechanism to control the regulation of R-loops.

“We have identified three main proteins in a ‘pathway’ that work together in a team to regulate the levels of R-loops and make them the optimum that’s needed for making proteins but also not big enough to induce DNA damage. This regulation is driven by a small molecule that’s added to proteins in our body called ubiquitin. In other words, we have found the protein that puts in the signal and the protein that takes it away.”

He said the findings could lead to new drugs to treat a variety of conditions.

“We could make drugs to increase this modification and therefore get rid of the moderator and therefore increase R-loops, which would be useful in killing cells, which is what we do when we treat people for cancer. The other application would be to reduce the level of R-loops, which could be beneficial for things like dementia and some genetic conditions that affect muscle co-ordination.”

He added: “Our next step at the Institute of Cancer Therapeutics in Bradford is to develop drugs for one or more of these proteins and we aim to start that next year.”

First author, former PhD student and current post-doctoral fellow, Mat Jurga said: “From day one, it’s been an exciting and fast-paced project – starting at the University of Sheffield and finishing at the University of Bradford. I think it is very lucky that we finished in the Institute of Cancer Therapeutics, as it is the perfect place to take the project forward and develop new drugs for cancer and dementia.

Not only have we shown how human cells fine-tune R-loops, but also how they deal with a loss of a protein – an event commonly found in cancer. Therefore, I’m looking forward to working with researchers from ICT and the University of Bradford to build on our findings and develop new drugs.”