The skin has a built-in defense against cancer, and sunlight turns it off

In a new study published in the journal Nature Communications, scientists from the University of Chicago examined how long-term exposure to ultraviolet (UV) radiation causes inflammatory responses in skin cells. They found that UV rays destroy the protein YTHDF2, which normally protects skin cells and prevents them from becoming cancerous. YTHDF2 plays a key role in regulating RNA metabolism to maintain cell health, and discovery of this mechanism may help develop new strategies for the prevention and treatment of skin cancer.

Ribonucleic acid (RNA) is the key molecule responsible for translating genetic information into proteins. An important role is played by non-coding RNAs, which regulate gene activity without synthesizing proteins. These molecules function either in the nucleus, where DNA is stored, or in the cytoplasm, where basic cellular processes occur. The lab studies how environmental stressors, including UV radiation and arsenic in drinking water, disrupt molecular pathways and damage cellular systems, promoting the development of cancer. In their experiments, the team found that ultraviolet light significantly reduced the level of the YTHDF2 protein in cells. YTHDF2 is an RNA “reader” that recognizes sequences with the chemical modification N6-methyladenosine (m6A).

Using multi-omics analyzes and additional cellular experiments, the researchers determined that the YTHDF2 protein binds to a specific non-coding RNA, U6, which is a small nuclear RNA (snRNA) and carries the m6A modification. When exposed to ultraviolet radiation, cancer cells accumulated increased amounts of U6 snRNA. These modified RNAs interacted with toll-like receptor 3 (TLR3), an immune sensor that can trigger inflammatory responses associated with cancer.

Unexpectedly, it turned out that these interactions occur inside endosomes – cellular compartments that are usually involved in the processing of substances, and do not serve as a medium for U6 snRNA. When YTHDF2 binds to the m6A-modified U6 RNA in endosomes, it blocks the ability of this RNA to activate TLR3. If YTHDF2 is missing, for example due to ultraviolet damage, U6 RNA is free to interact with TLR3, causing inflammation.