Cancer research, drug safety testing and ageing biology may all gain a major boost from a new fluorescent sensor developed at Utrecht University. This new tool allows scientists to watch DNA damage and repair unfold in real time inside living cells. The development, which opens the door to experiments that weren't feasible before, is published today in the journal Nature Communications.
DNA inside our cells is constantly damaged by sunlight, chemicals, radiation or simply by the many processes that keep us alive. Usually, the cell fixes this damage quickly and efficiently. But when repair fails, the consequences can be serious, contributing to ageing, cancer and other diseases.
Until now, however, scientists had great difficulty watching these repair processes as they happen. Most methods required killing and fixing cells at different moments, offering only snapshots of the action.
DNA damage sensor
Researchers at Utrecht University have now developed a tool that changes this completely. They developed a DNA damage sensor that allows scientists to observe how damage forms and disappears in living cells and even in living organisms. The study, published this week in Nature Communications, opens a door to experiments that were impossible before.
Lead researcher Tuncay Baubec describes the innovation as a way to look into the cell "without disrupting the cell". He explains that existing tools, such as antibodies or nanobodies, tend to bind too strongly to DNA. Once attached, they can interfere with the cell's own repair machinery.
"Our sensor is different," he says. "It's built from parts taken from a natural protein that the cell already uses. It goes on and off the damage site by itself, so what we see is the genuine behaviour of the cell."
"This is going to work"
The sensor works by attaching a fluorescent tag to a tiny domain borrowed from one of the cell's own proteins. This domain briefly binds to a marker that appears on damaged DNA. Because the interaction is gentle and reversible, it lights up the damage without blocking the repair process.
Biologist Richard Cardoso Da Silva , who engineered and tested the tool, remembers clearly when he realised they had something special. "I was testing some drugs and saw the sensor lighting up exactly where commercial antibodies did," he says. "That was the moment I thought: this is going to work."
A more realistic picture
The difference with earlier methods is dramatic. Instead of labouring through ten separate experiments to capture ten time points, scientists can now follow the entire repair process in one continuous movie. They can see when damage appears, how quickly repair proteins arrive, and when the cell finally resolves the problem. "You get more data, higher resolution and, importantly, a more realistic picture of what actually happens inside a living cell," says Cardoso Da Silva.
From cells in the lab to living organisms
The team did not stop at cultured cells. Collaborators at Utrecht University tested the protein in the worm C. elegans, a living organism widely used in biology. The sensor performed just as well there, and revealed programmed DNA breaks that form during the worm's development. For Baubec, this was a key moment. "It showed that the tool is not only for cells in the lab. It can be used as well in real living organisms."
Discovering what affects repair
The possibilities now stretch far beyond observing repair. The protein can be freely attached to other molecular parts. This means researchers can use it to map where DNA damage occurs in the genome, and also identify which proteins gather around a damaged spot. They can even move damaged DNA to different locations inside the cell nucleus to see what factors affect repair. "Depending on your creativity and your question, you can use this tool in many ways," says Cardoso Da Silva.
More accurate medical research
Although the sensor itself is not a medical treatment, it could influence medical research. Many cancer therapies act by deliberately damaging the DNA of tumour cells. In early drug development, scientists need to measure exactly how much DNA damage a compound causes.
"Right now, clinical researchers often use antibodies to assess this," Baubec says. "Our tool could make these tests cheaper, faster and more accurate." The researchers also imagine uses in clinical practice, from studying natural ageing processes to detecting radiation or mutagenic exposure.
Available for all researchers
Their tool has already attracted attention. Other laboratories contacted them even before publication, eager to use the sensor in their own research on DNA repair. To support that, the team has made the tool openly available. Baubec: "Everything is online. Scientists can use it immediately."
