DNA repair proteins serve as the body’s molecular editors, constantly detecting and fixing damage to our genetic code. One such protein, polymerase theta (Pol-theta), has been a critical focus in cancer research for its role in aiding the survival of cancer cells. For years, scientists have been working to understand how cancer cells exploit Pol-theta to bypass standard DNA repair mechanisms. Now, a team at Scripps Research has made a significant breakthrough by capturing the first high-resolution images of Pol-theta in action, offering crucial insights into its role in cancer development.
Published in Nature Structural & Molecular Biology on February 28, 2025, the study reveals that Pol-theta undergoes a significant structural change when binding to broken DNA strands, shedding light on how it functions in cancer cells. This discovery provides a foundation for developing more targeted and effective cancer therapies aimed at blocking Pol-theta’s activity.
Pol-theta: A Key Enzyme in Cancer Cell Survival
Pol-theta is an enzyme that speeds up chemical reactions necessary for repairing DNA damage, a constant issue for cells. Normally, cells employ precise and accurate repair mechanisms to fix DNA breaks, but certain cancers—especially those linked to BRCA1 or BRCA2 mutations (such as some breast and ovarian cancers)—lack these mechanisms. Instead, they rely on Pol-theta, a more error-prone repair process.
“Pol-theta is a critical target for cancer treatment, and many pharmaceutical companies view it as a promising approach to treat cancers with defective DNA repair pathways,” says Christopher Zerio, the first author of the study and a former postdoctoral fellow in Lander’s lab.
Though earlier research identified parts of Pol-theta’s structure, its specific interactions with DNA remained unclear. “What’s been missing is how Pol-theta engages with DNA, which is key for developing drugs to target it,” explains Zerio.
Revealing Pol-theta in Action
Prior to this study, Pol-theta was known to exist in two forms: a tetramer (four copies of the enzyme) and a dimer (two copies). However, scientists did not know what caused the enzyme to switch between these forms. Pol-theta’s structure had only been captured in its inactive state, leaving a major gap in understanding how it interacts with DNA.
Using cryo-electron microscopy and biochemical experiments, the team made a groundbreaking discovery: When Pol-theta binds to broken DNA strands, it consistently shifts from its tetrameric form to a dimeric configuration. This shift was previously unknown, and it’s crucial for the enzyme’s function in DNA repair.
Once Pol-theta is in its active state, it follows a two-step process to repair DNA. First, the enzyme searches for “microhomologies”—small matching sequences—on broken DNA strands. Once it finds a match, Pol-theta holds the strands together, allowing them to naturally bond without needing additional energy. This unique feature of Pol-theta distinguishes it from most other enzymes, which require an energy boost to function.
“If we can block this process, we could make Pol-theta-dependent cancers much more sensitive to treatment,” says Zerio.
A Promising Target for Cancer Therapies
Pol-theta is produced at low levels in healthy cells, which makes it an appealing target for cancer treatments. Healthy cells rely on more accurate, energy-dependent repair mechanisms, while cancer cells exploit Pol-theta due to defective DNA repair pathways. This difference means that inhibiting Pol-theta could specifically target cancer cells without causing significant harm to healthy tissue.
“Most cancer drugs target proteins that are also needed by healthy cells,” says senior author Gabriel Lander, a professor at Scripps Research. “By targeting Pol-theta, we can potentially kill cancer cells while minimizing side effects for healthy tissue.”
Drugs that inhibit Pol-theta are already undergoing clinical trials, although they often require combination therapies to work effectively. This study offers new possibilities for creating more precise therapies, potentially leading to treatments that target BRCA-associated cancers more effectively.
As the research progresses, the team at Scripps is also exploring the broader role of Pol-theta in DNA repair. “We want to understand why Pol-theta exists in its tetrameric form and how it interacts with other DNA repair enzymes,” says Lander. “These insights could open up new strategies for treating BRCA-related cancers.”
With these critical advancements, the study of Pol-theta brings hope for more targeted cancer therapies that could ultimately improve treatment outcomes for patients with specific genetic mutations.
By Impact Lab
