An enzyme called DNA polymerase theta plays a key role in repairing DNA damage to cancer cells, helping the cancer survive the toxic environment it creates through the process of its own growth. Now a study published recently in Nature Communications explains the surprising spatiotemporal mechanism through which this enzyme is delivered and activated at the site of damage.
The findings suggest a new and previously unknown potential therapeutic target that could be blocked by inhibitors to destroy cancer cells. “It’s an important discovery because DNA polymerase theta is known to play a critical role in several types of cancer, including BRCA1- and BRCA2-deficient tumors, as well as leukemia,” said senior author Tomasz Skorski, MD, PhD, DSc, Director of the Fels Cancer Institute for Personalized Medicine and a Professor in the Department of Cancer and Cellular Biology at the Lewis Katz School of Medicine at Temple University. He is also a Program Co-Leader for the Nuclear Dynamic and Cancer Research Program at Fox Chase Cancer Center.
Inhibitors targeting DNA polymerase theta are already in clinical trials, and they are seen as a promising potential treatment for several cancers. For the new study, researchers wanted to understand how the enzyme is activated.
They focused on a process called PARylation, which is known to be a common mechanism for regulating many DNA repair enzymes. This mechanism typically works like a simple “on-off” switch, with an enzyme called PARP1 causing PARylation and a different enzyme called PARG exerting de-PARylation. These phenomena used to play opposite roles in regulating the activity of DNA repair proteins.
But that’s not what the scientists found this time. Instead, they discovered that the two enzymes worked together to promote DNA polymerase theta activity, with PARP1 causing the delivery of DNA polymerase theta to the site of DNA damage, followed by PARG activating the polymerase so it could begin making repairs.
“We thought PARP1 would activate DNA polymerase theta and PARG would inactivate it, and we were completely wrong,” Skorski said. “We found a very unique and unusual process where these two counteractive mechanisms actually work together.”
The current generation of inhibitors targeting DNA polymerase theta focus on blocking its enzymatic activity with small molecule drugs. Skorski’s finding suggests that simultaneously blocking DNA polymerase theta and PARG or PARP1 could be even more effective by shutting down the enzyme that’s already on site in cancer cells or preventing any more from being delivered. This dual approach could also prevent the cancer from becoming resistant to treatment.
“This could give us an opportunity to potentially combine inhibitors for a better, stronger antitumor effect,” said Skorski, who conducted the study with other researchers at the Fels Institute, as well as members of the Department of Biochemistry and Molecular Biology at Thomas Jefferson University, led by co-senior author Richard T. Pomerantz, PhD.
Next, the researchers want to study whether the same mechanism occurs in leukemia cells. Leukemia is already known to be highly sensitive to DNA polymerase theta inhibition, so confirming the findings and identifying a second target could lead to even more effective and durable therapies.
The research was funded by the National Institutes of Health and the Leukemia and Lymphoma Society. The title of the study is “PARG is Essential for Polθ-Mediated DNA End-Joining by Removing Repressive Poly-ADP-Ribose Marks.”