Unraveling How DNA Damage Leads to Disease

Consider looking at a photo of the Grand Canyon compared to hiking through it. The two-dimensional photo is flat and lacks depth. On your hike, you perceive depth and distance. You can explore the rock formations from different angles. Now imagine being able to do that with a DNA strand. 

Structural biology focuses on understanding the three-dimensional (3D) structures of biomolecules, as well as how these structures function and interact with each other during cellular processes. Using the latest technologies, structural biologists like Bret Freudenthal, PhD, can investigate every nook and cranny of molecular structures.

Dr. Freudenthal is an associate professor of biochemistry and molecular biology at the University of Kansas Medical Center, and he has dedicated his career to better understanding how DNA damage is repaired to protect the genome. This knowledge is important because a molecule's structure dictates its biological function, and DNA damage promotes dangerous genomic mutations.

DNA plays a crucial role in the development and progression of cancer. While there are many factors involved in cancer development, changes to the cellular DNA arising from DNA damage is a basic driver of multiple human diseases. For example, skin cancer can arise if DNA is damaged after excessive exposure to ultraviolet radiation from the sun. 

Untangling the complexity of our DNA to better understand how it influences our health is a monumental task, to say the least. Each human cell has about 6 feet of DNA, and the human body contains around 10 trillion cells. Researchers estimate that each person has around 10 billion miles of DNA inside of them. The packing of the DNA into compact structures helps keep the DNA organized in the cell's nucleus, which is typically a few micrometers in diameter.

Dr. Freudenthal is interested in what is going on in the nucleus bundles - how proteins are identifying and repairing DNA damage. Understanding DNA damage and repair mechanisms is a crucial step forward in the development of better therapies. With this knowledge, researchers can develop approaches to manipulate the DNA damage response to treat and prevent disease.

“Not all DNA damage is processed the same way. You need specialized structural biology tools that give you a high-resolution view to see how DNA damage is repaired at the atomic level,” Dr. Freudenthal says. “This information is essential to understanding the mechanism by which the human genome is damaged and subsequently repaired to prevent deleterious mutations.” 

To understand how proteins interact with DNA and repair damage, Dr. Freudenthal’s research relies on leading-edge technology. His team regularly utilizes X-ray crystallography, a sophisticated technique that visualizes the arrangement of atoms within a crystal. His team was also among the first to try out the University of Kansas Medical Center’s new cryogenic electron microscope, which arrived on campus April 2023. Known as “cryo-EM,” the tool produces 3D images of biological samples at an extremely high resolution. Unlike traditional electron microscopes, which require samples to be dehydrated and stained, cryo-EM allows for the visualization of samples in their natural state, which is crucial for studying biological molecules and structures accurately. The purchase of the microscope was partially funded by $1 million in congressionally directed spending.

“When you’re developing a drug target, you must know the precise area the drug will bind,” Dr. Freudenthal explains. “You have to have an intimate understanding of the target, and you can’t do that without using advanced techniques like cryo-EM or X-ray crystallography.”

Nurturing Future Investigators 

As Dr. Freudenthal progressed in his career, he came to recognize the influence he can have by mentoring young researchers in their career development. Academic medical centers like The University of Kansas Cancer Center play a crucial role in growing the future research workforce by fostering an environment that encourages education, training and research. Watching the young members of his lab move on to “bigger and better things” in their career is a huge point of pride for Dr. Freudenthal.

“They have a true love and excitement for science. Watching them advance not only the science but their careers is one of the highlights of my job,” Dr. Freudenthal says.