DNA repair proteins Act like the authors of the body, constantly finding and reversing the damage to our genetic code. Researchers have struggled a lot to understand how cancer cells deceive one of these proteins called the Polymerase Proteins Theta (Pol-Teta)-for their own survival. But scripps research scientists have now recorded the first detailed Pol-Teta images in action, revealing the molecular processes responsible for a series of cancers.
The findings published in the Structural and molecular biology of nature On February 28, 2025, they illuminate the way Pol-Teta undergoes a significant structural rearrangement when bound with broken DNA. By revealing the structure of POL-TETA DNA-the active state-The study provides a plan for designing more effective cancer drugs.
We now have a much clearer picture of the way Pol-Teta works, which will allow us to prevent its activity more accurately. ”
Gabriel Lander, Senior Author, Professor at Scripps Research
Technically, Pol-Teta is a type of protein that speeds up chemical reactions, including those related to cell repair. DNA damage is a stable problem for cells, which occur millions of times a day collectively throughout our body. Cells usually use extremely accurate mechanisms to correct these breaks, but some cancers-brackets resulting from BRCA1 or BRCA2 mutations, such as some breast and ovarian cancers. Instead, they depend on a more honest method controlled by Pol-Teta.
“Pol-Teta is an important goal and many pharmaceutical companies see it as a promising way to deal with cancers with defective DNA repair routes,” adds first writer Christopher Zerio, a former postdoctoral collaborator at Lander’s Laboratory.
Although previous studies have mapped parts of the Pol-Teta structure, enzyme interactions with DNA were not well understood.
“What is missing is how Pol-Teta is actually involved in DNA, which is essential for the development of drugs,” says Zerio.
Previous research has shown that Pol-Teta exists in two forms: one quadruple (four copies of the enzyme) and one bilateral (two copies). But why either Pol-Teta changed between these forms was unknown.
Prior to this study, the structure of Pol-Teta was only captured in inactive state, leaving a significant gap of knowledge about how the enzyme interacts with DNA. It was like trying to determine how a bee looks forward to nectar when all you have seen is a closed flower.
“You know that interaction should happen, but without seeing it, the mechanism remains a mystery,” Lander explains.
Using cryo-electron microscopy and biochemical experiments, the group made a stunning discovery, while recording Pol-teta in DNA repair: Every time Pol-Teta is bound to broken clones, it was firmly converted from four-day to an endless configuration.
Once active, Pol-Teta repairs DNA using a two-stage process: first, the enzyme searches for small matching sequences called “micro-monologues” on broken strands. Once a corresponding sequence is detected, Pol-Teta holds the broken DNA clones with the broken DNA clones so that they can sew them together without the need for extra energy. Most enzymes require an energy impulse to function, but Pol-teta is based on the natural attraction between the corresponding DNA sequences, allowing them to break their position on their own.
“If we can exclude this process, we could make the Pol-Teta cancers dependent much more sensitive to treatment,” Zerio says.
It is important that Pol-Teta is produced at low levels in healthy cells, making it a promising target for cancer treatments. Unlike cancerous cells, which depend on Pol-Teta as an alternative to defective repair routes, healthy people are based on more accurate repair mechanisms that require more accurate repair of DNA that allows for energy rehabilitation. Because healthy cells do not need pol-teta for survival, preventing enzyme activity will probably not cause wide damage to healthy tissue.
“Most cancer drugs are targeting proteins that are also needed by healthy cells,” Lander notes. “Specifically, targeting Pol-Teta should only kill cancer cells, reducing the likelihood of side effects during treatment.”
Medicines that inhibit Pol-Teta are already in clinical trials, but today they need to be combined with other treatments to work effectively. While this study could update the most accurate development of drugs, further research may reveal other roles that can play the enzyme in cellular functions.
“We also want to understand why there is Pol-Teta in its quadric form and how it interacts with other DNA repair enzymes,” says Lander. “Such knowledge could lead to new BRCA -related cancer ways.”
In addition to Lander and Zerio, the authors of the study, “Human polymerase helicosis DNA Places for Double Plot Repair”, include Yonghong Bai, Brian A. Sosa-Alvarado and Timothy Guzi by Moma Therapeutics.
This project was supported by the funding by the National Institutes of Health (F32CA288144, GM14305 and S10OD032467).
Source:
Magazine report:
Zerio, CJ, et al. (2025). Human polymerase helicosis DNA Polomatics Micro -bishops for double -propelle repair. Structural and molecular biology of nature. Doi.org/10.1038/S41594-025-01514-8.
