New mechanism discovered that triggers immune response in cells with damaged DNA

(Press-News.org) Irvine, Calif., Jan. 6, 2025 — A research team from the University of California, Irvine has revealed a previously unknown mechanism that triggers an inflammatory immune response in cells when their DNA is damaged. This discovery deepens the understanding of a new type of cell signaling that may lead to more effective treatments for cancer.

 

The study, published online today in the journal Nature Structural & Molecular Biology, found that UV irradiation or certain chemotherapeutic drugs activate a specific response when cells are too damaged to be repaired correctly, preventing them from becoming cancerous.

 

“This discovery could have significant implications for cancer treatment,” said corresponding author Rémi Buisson, UC Irvine associate professor of biological chemistry. “Understanding how different cancer cells react to DNA damage could lead to more tailored and effective therapies, potentially reducing negative side effects and improving the quality of life for patients.”

 

Scientists have long understood that when both DNA strands are broken, the ATM enzyme triggers the activation of the protein NF-κB within the cell, leading to the production of inflammatory signals. In this study, spearheaded by postdoctoral fellow Elodie Bournique and assisted by graduate student Ambrocio Sanchez, it was shown that when DNA damage occurs due to UV exposure or treatment with chemotherapeutic drugs such as actinomycin D or camptothecin, the IRAK1 enzyme induces NF-κB to send out signals to recruit immune cells.

 

Team members developed an advanced imaging technique to analyze how NF-κB is regulated at the cellular level. The researchers were able to precisely measure a cell’s response to damaged DNA at the single-cell level and observed a new pathway to the activation of NF-κB. They found that after specific types of injury, cells release the IL-1α protein. It doesn’t act on the cell itself but travels to neighboring cells, where it triggers the IRAK1 protein, which then initiates the NF-κB inflammatory response.

 

“Our findings will help us better understand the consequences of certain types of chemotherapeutic drugs that are used to treat patients and cause DNA damage. We’ve discovered that the IL-1α and IRAK1 proteins, which play a role in the immune process, vary significantly across different cancer cell types. This suggests that not all patients will react to treatment in the same way, Buisson said. “By assessing these protein levels ahead of time, doctors might be able to personalize therapies tailored to individual patients’ needs for improved success rates.”

 

The researchers will continue their work by testing their findings on mouse models that lack specific factors involved in the new pathway.

 

Other team members from the School of Medicine’s Department of Biological Chemistry were Professor Ivan Marazzi; Associate Professor Selma Masri; postdoctoral fellow Pedro Ortega; graduate students Sunwoo Oh, Alisa Mahieu, Lavanya Manjunath, Eirene Ednacot; and undergraduate researcher Daniel Ghazarian.

 

This work was supported by the National Institutes of Health’s Research Supplements to Promote Diversity in Health-Related Research program under award R37-CA252081-S1; a National Science Foundation Graduate Research Fellowship under award DGE-1839285; California Institute for Regenerative Medicine stem cell biology training grant TG2-01152; European Molecular Biology Organization postdoctoral fellowship ALTF 213-2023; NIH awards R37-CA252081, R01-CA244519, R01-CA259370, R01-AI168130 and U01-AU150748; American Cancer Society Research Scholar Grant RSF-24-1249960-01-DMC; the Concern Foundation; a University of California Cancer Research Coordinating Committee award; a Center for Virus Research Graduate Fellowship funded by the UC Irvine Faculty Mentor Program; the School of Medicine Office of Graduate Studies; and access to the Genomics Research and Technology Hub Grant P30-CA62203.

 

About the University of California, Irvine: Founded in 1965, UC Irvine is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UC Irvine has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UC Irvine, visit www.uci.edu.

 

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