A research team has uncovered a previously unrecognized mechanism that triggers an inflammatory immune reaction in cells when their DNA sustains damage. This finding enhances our comprehension of a novel form of cellular signaling that could pave the way for improved cancer treatments.
Researchers from the University of California, Irvine have discovered a previously unknown process that initiates an inflammatory immune response in cells upon DNA damage. This finding enhances our understanding of a new form of cellular signaling, which may lead to more effective cancer therapies.
The findings were published today in the journal Nature Structural & Molecular Biology. The study revealed that exposure to UV light or certain chemotherapy drugs ignites a distinct response when cells are excessively damaged to be repaired, thereby preventing them from turning cancerous.
“This revelation could greatly influence cancer treatment,” stated Rémi Buisson, an associate professor of biological chemistry at UC Irvine and the study’s lead author. “By gaining insight into how various cancer cells respond to DNA damage, we can develop more customized and efficient treatments, potentially minimizing side effects and enhancing patient quality of life.”
Researchers have long known that when both strands of DNA are broken, the ATM enzyme activates the NF-κB protein in the cell, which leads to the generation of inflammatory signals. This study, led by postdoctoral fellow Elodie Bournique and graduate student Ambrocio Sanchez, demonstrated that UV damage or chemotherapeutic agents like actinomycin D or camptothecin prompts the IRAK1 enzyme to stimulate NF-κB, which then signals the recruitment of immune cells.
The research team developed an advanced imaging technique to investigate how NF-κB is regulated at the cellular level. They successfully measured the cellular response to DNA damage at an individual cell scale and discovered a new approach to activating NF-κB. Their observations showed that after specific injuries, cells release IL-1α protein. Rather than affecting the cell itself, it communicates with neighboring cells, activating the IRAK1 protein which subsequently initiates the NF-κB inflammatory response.
“Our research will enhance understanding of the effects of various chemotherapeutic drugs that inflict DNA damage on patients. We’ve found that the IL-1α and IRAK1 proteins—key players in the immune response—differ significantly among various cancer cell types. This indicates that treatment responses may vary among patients,” Buisson explained. “By evaluating these protein levels in advance, healthcare providers might personalize therapies according to individual patient needs, leading to improved treatment outcomes.”
The team plans to further their research by testing their findings on mouse models that lack key components of the newly identified pathway.
Other contributors to this research from the School of Medicine’s Department of Biological Chemistry included 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 research was funded 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 support from the Genomics Research and Technology Hub Grant P30-CA62203.
