Newswise — Researchers have identified a pathway that triggers an immune response in cells with defective DNA repair. In particular, the authors of a new paper demonstrated how the downregulation of AUF1 impairs DNA repair, followed by activation of the immune response due to the presence of R-loops in the cytoplasm. This represents an important finding for the development of new therapeutic strategies aimed at modulating the immune response upon DNA damage.
The investigation was carried out through an international collaboration between leading scientific institutions in precision medicine, including the Sbarro Health Research Organization (SHRO), the National Cancer Institute “Pascale Foundation,” and the Scuola Superiore Meridionale of Naples. Researchers identified the RNA-binding protein AUF1 as a key regulator at the crossroads of genome stability and immune activation.
The study, “The modulation of AUF1 regulates the R-loop resolution activating the immune response in DDR,” was published last month in the journal iScience.
Connecting DNA Damage to Immune Response
Cells are constantly exposed to DNA damage, which induces a cellular function known as the DNA Damage Response (DDR). While traditionally viewed as a repair system, DDR is now recognized as a complex process that modulates the Tumour Microenvironment (TME).
“Understanding and leveraging this relationship could pave the way for more precise and effective cancer therapies,” says Prof. Antonio Giordano, M.D., Ph.D., Director of the Sbarro Institute for Cancer Research and Molecular Medicine, Founder and President of the SHRO, and Professor at Temple University.
At the center of this process is a hybrid DNA and RNA structure called an R-Loop. Under normal conditions, these structures play physiological roles, but when dysregulated, they can accumulate and trigger a cellular stress response.
When AUF1 is depleted or dysfunctional, R-loops build up in the cytoplasm and activate the cGAS–STING signaling pathway, leading to the production of interferons and other inflammatory molecules crucial for anti-tumor immunity. Understanding how this occurs naturally, doctors are figuring out how they might directly modulate R-loops to trigger the immune system response and target tumor cells for destruction.
These findings position AUF1 as a potential therapeutic target as a readout of immune activation and modulation.
“This work highlights how tightly interconnected DNA repair and immune signaling are,” says Dr. Luigi Alfano, a researcher at the National Cancer Institute of the Pascale Foundation.
Overall, the study reinforces the idea that cancer is not just driven by uncontrolled cell growth, but by complex interactions between genomic instability, cellular processes, and the immune system.
Targeting these interconnected pathways may represent a powerful strategy for the next generation of cancer treatments.
About Sbarro Health Research Organization (SHRO)
The Sbarro Health Research Organization conducts groundbreaking research in cancer, diabetes, and cardiovascular disease. Based in Philadelphia, Pennsylvania, on the campus of Temple University, SHRO’s programs train young scientists from around the globe, accelerating the pace of health research and innovation.