DNA in our cells faces continual harm from sunlight, chemicals, radiation and even the normal processes that keep the body functioning. Most of this damage is corrected very quickly. When these repairs fail, the resulting errors can play a role in aging, cancer and several other diseases.

For years, researchers struggled to directly observe these repair events as they occurred. Many traditional approaches required killing and preserving cells at different time points, producing only isolated snapshots instead of a continuous view.

A New DNA Damage Sensor for Living Cells

Scientists at Utrecht University have now introduced a sensor that changes this situation. Their tool allows researchers to watch damage appear and fade inside living cells and also inside living organisms. According to the study published in Nature Communications, this capability opens the way to experiments that were previously out of reach.

Lead researcher Tuncay Baubec describes the approach as a method for looking inside a cell "without disrupting the cell." He notes that common tools such as antibodies and nanobodies often bind too tightly to DNA, which can interfere with the cell's own repair systems.

"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 behavior of the cell."

How the Fluorescent Sensor Works

The system relies on a fluorescent tag attached to a small domain taken from one of the cell's own proteins. This domain briefly recognizes a marker that appears only on damaged DNA. Because the interaction is gentle and reversible, the sensor highlights the affected region while leaving the cell's repair work untouched.

Biologist Richard Cardoso Da Silva, who helped design and evaluate the tool, recalls the moment he recognized its potential. "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 Continuous View of DNA Repair

The contrast with older methods is striking. Instead of running many separate experiments to capture different moments, researchers can now watch the entire repair sequence as a single continuous movie. They can track when the damage appears, observe how rapidly repair proteins arrive and see when the cell resolves the issue. "You get more data, higher resolution and, importantly, a more realistic picture of what actually happens inside a living cell," says Cardoso Da Silva.

The research team also tested the sensor outside the lab dish. Collaborators at Utrecht University used the tool in the worm C. elegans, a widely used model organism. The sensor performed equally well and revealed programmed DNA breaks that occur during the worm's development. For Baubec, this demonstration was essential. "It showed that the tool is not only for cells in the lab. It can be used as well in real living organisms."

The potential applications extend beyond watching repair occur. The sensor's protein domain can be connected to other molecular components, allowing scientists to map the locations of DNA damage across the genome or determine which proteins gather around a damaged region. Researchers can also reposition damaged DNA inside the nucleus to test how its location influences repair. "Depending on your creativity and your question, you can use this tool in many ways," says Cardoso Da Silva.

Better Tools for Medical and Drug Research

Although the sensor is not a treatment, it could significantly improve medical research. Many cancer therapies work by inflicting deliberate DNA damage on tumor cells, and early drug development often requires precise measurements of how much damage a compound creates.

"Right now, clinical researchers often use antibodies to assess this," Baubec says. "Our tool could make these tests cheaper, faster and more accurate." The team also sees potential uses in clinical settings, such as studying natural aging or detecting exposure to radiation or other mutagenic factors.

The innovation is already attracting interest. Several laboratories contacted the team before publication, eager to use the sensor in their own repair studies. To support this demand, the researchers have made the tool available without restrictions. Baubec notes, "Everything is online. Scientists can use it immediately."

"Astrocytes perform diverse tasks that are essential for normal brain function, including facilitating brain communications and memory storage. As the brain ages, astrocytes show profound functional alterations; however, the role these alterations play in aging and neurodegeneration is not yet understood," said first author Dr. Dong-Joo Choi, who conducted this work while at the Center for Cell and Gene Therapy and the Department of Neurosurgery at Baylor. Choi is now an assistant professor at the Center for Neuroimmunology and Glial Biology, Institute of Molecular Medicine at the University of Texas Health Science Center at Houston.

Focusing on Sox9 as a Key Regulator

For this project, the investigators set out to understand how astrocytes change with age and how those changes relate to Alzheimer's disease. Their attention centered on Sox9, a protein that influences a wide network of genes involved in astrocyte aging.

"We manipulated the expression of the Sox9 gene to assess its role in maintaining astrocyte function in the aging brain and in Alzheimer's disease models," explained corresponding author Dr. Benjamin Deneen, professor and Dr. Russell J. and Marian K. Blattner Chair in the Department of Neurosurgery, director of the Center for Cancer Neuroscience, member of the Dan L Duncan Comprehensive Cancer Center at Baylor and principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.

Testing the Approach in Symptomatic Alzheimer's Models

"An important point of our experimental design is that we worked with mouse models of Alzheimer's disease that had already developed cognitive impairment, such as memory deficits, and had amyloid plaques in the brain," Choi said. "We believe these models are more relevant to what we see in many patients with Alzheimer's disease symptoms than other models in which these types of experiments are conducted before the plaques form."

In these models, the researchers either increased or removed Sox9 and then monitored each mouse's cognitive performance for six months. During this period, the animals were tested on their ability to recognize familiar objects and locations. After the behavioral studies were completed, the team examined the brains to measure plaque accumulation.

Higher Sox9 Levels Improve Plaque Removal and Memory

The results showed a clear difference. Lowering Sox9 led to faster plaque buildup, reduced structural complexity in astrocytes and diminished plaque clearing. Raising Sox9 had the opposite effect, increasing the cells' activity, supporting plaque removal and preserving cognitive performance. The protective benefits suggested that strong astrocyte engagement may help slow the cognitive decline associated with neurodegenerative disease.

"We found that increasing Sox9 expression triggered astrocytes to ingest more amyloid plaques, clearing them from the brain like a vacuum cleaner," Deneen said. "Most current treatments focus on neurons or try to prevent the formation of amyloid plaques. This study suggests that enhancing astrocytes' natural ability to clean up could be just as important."

Future Potential and Ongoing Research Needs

Choi, Deneen and their colleagues note that additional research is needed to understand how Sox9 behaves in the human brain across time. Still, these results point toward the possibility of developing therapies that harness astrocytes' natural cleaning abilities to combat neurodegenerative disorders.

Sanjana Murali, Wookbong Kwon, Junsung Woo, Eun-Ah Christine Song, Yeunjung Ko, Debo Sardar, Brittney Lozzi, Yi-Ting Cheng, Michael R. Williamson, Teng-Wei Huang, Kaitlyn Sanchez and Joanna Jankowsky, all at Baylor College of Medicine, also contributed to this work.

This research was supported by National Institutes of Health grants (R35-NS132230, R01-AG071687, R01-CA284455, K01-AG083128, R56-MH133822). Additional funding came from the David and Eula Wintermann Foundation, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number P50HD103555 and from shared resources provided by Houston Methodist and Baylor College of Medicine.