Scientists have uncovered how too much sunlight can flip a hidden switch inside skin cells that makes inflammation spiral out of control and increases the risk of cancer. Their research reveals that UV radiation breaks down a protective protein called YTHDF2, which usually prevents a small RNA signal from activating an immune sensor linked to dangerous inflammation. Once that protection is lost, a surprising chain reaction unfolds inside the cell, turning ordinary sun damage into a potential cancer trigger
Sunlight plays a vital role in human health because it helps the body synthesise essential nutrients, such as vitamin D. However, spending too much time in the sun can significantly increase the risk of developing skin cancer.
In a new study in Nature Communications, scientists at the University of Chicago report that long-term exposure to ultraviolet (UV) radiation can trigger inflammatory responses in skin cells by degrading a key protein called YTHDF2. This protein acts as a gatekeeper, helping prevent normal skin cells from turning cancerous. The researchers showed that YTHDF2 is central to regulating RNA metabolism, thereby maintaining cell health, and their work points to potential new strategies for preventing and treating skin cancer.
UV Radiation, Inflammation, and Rising Skin Cancer Cases
Every year, almost 5.4 million people in the United States receive a skin cancer diagnosis, and more than 90% of these cases are linked to excessive UV exposure. UV radiation can injure DNA and generate oxidative stress in skin cells, which in turn triggers inflammation that causes the familiar redness, pain, and blistering of sunburn.
“We’re interested in understanding how inflammation caused by UV exposure contributes to the development of skin cancer,” said Yu-Ying He, PhD, Professor of Medicine in the Section of Dermatology at the University of Chicago.
RNA, or ribonucleic acid, is a crucial molecule that helps translate genetic information into proteins. A critical group of RNA molecules, known as non-coding RNAs, regulates gene activity without making proteins. These non-coding RNAs usually function either in the nucleus, where the cell’s DNA is located, or in the cytoplasm, where most cellular processes occur.
How YTHDF2 Helps Protect Skin Cells
His laboratory focuses on how environmental stressors, including UV radiation and arsenic in drinking water, disrupt molecular pathways and damage cellular systems in ways that promote cancer. In their experiments, the team screened multiple enzymes and found that UV exposure significantly reduced YTHDF2 levels in cells. YTHDF2 is a “reader” protein that recognises RNA sequences explicitly tagged with a chemical modification called N6-methyladenosine (m6A).
“When we removed YTHDF2 from skin cells, we saw that UV-triggered inflammation was much worse,” He said. “This suggests that the YTHDF2 protein plays a key role in suppressing inflammatory responses.”
Inflammation is vital for defending the body against infections, but if it is not carefully controlled, it can drive serious diseases, including cancer. The detailed molecular mechanisms that keep this response in check after UV damage, however, remain poorly understood.
Non-Coding RNA, Immune Sensors, and UV Stress
Using multi-omics approaches and additional cell-based tests, the researchers showed that YTHDF2 binds to a specific non-coding RNA, U6, which carries an m6A modification and is classified as a small nuclear RNA (snRNA). Under UV stress, cancer cells accumulated higher levels of U6 snRNA, and these modified RNAs were found to interact with toll-like receptor 3 (TLR3), an immune sensor known to trigger inflammatory pathways associated with cancer.
Unexpectedly, these interactions occurred within endosomes, cellular compartments that usually help recycle materials rather than serve as a host for U6 snRNA.
“We spent a lot of time figuring out how these non-coding RNAs get to the endosome, since that’s not where they usually reside,” He explained. “For the first time, we showed that a protein called SDT2 transports U6 into the endosome, and YTHDF2 travels with it.”
A Cellular Surveillance System Against Excessive Inflammation
Once YTHDF2 and m6A-modified U6 RNA reach the endosome, YTHDF2 prevents the RNA from activating TLR3. When YTHDF2 is missing, as after UV-induced damage, U6 RNA can bind freely to TLR3, triggering harmful inflammatory responses.
“Our study uncovers a new layer of biological regulation, a surveillance system through YTHDF2 that helps protect the body from excessive inflammation and inflammatory damage,” He said.
This newly described pathway suggests potential strategies for preventing or treating UV-induced skin cancer by targeting the interactions between RNA and proteins that control inflammation.
The study, “YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis,” was supported by grants from the National Institutes of Health, the University of Chicago Medicine Comprehensive Cancer Centre, the ChicAgo Centre for Health and Environment (CACHET), and the University of Chicago Friends of Dermatology Endowment Fund.
