Scientists reveal surprising truth: DNA damage not the main culprit in sunburns


Scientists reveal surprising truth: DNA damage not the main culprit in sunburns

COPENHAGEN -- Most people associate sunburns with DNA damage -- it's what we've been taught in textbooks and by dermatologists for years. However, surprising new research suggests that it's actually RNA damage triggering the acute inflammatory reactions we experience as sunburn.

A team of researchers from the University of Copenhagen and Nanyang Technological University, Singapore investigated how skin cells respond to UV exposure, focusing on a protein called ZAKα. This protein acts as a cellular stress sensor, detecting when UV radiation has damaged messenger RNA (mRNA) molecules involved in protein production. Unlike DNA, which is long-lived and passes mutations down to future cells, RNA is more transient and experiences damage regularly without causing permanent mutations.

"Sunburn damages the DNA, leading to cell death and inflammation. So the textbooks say. But in this study we were surprised to learn that this is a result of damage to the RNA, not the DNA that causes the acute effects of sunburn," explains Anna Constance Vind, an assistant professor from the Department of Cellular and Molecular Medicine at Copenhagen, in a statement.

The study, published in Molecular Cell, revealed that mRNA damage triggers a response in ribosomes -- cellular protein-making factories -- orchestrated by ZAKα through what's called the ribotoxic stress response. This surveillance system within cells registers RNA damage, leading to inflammatory signaling and immune cell recruitment that causes skin inflammation.

To investigate this mechanism, the researchers used genetically modified mice lacking the ZAK gene. When exposed to UV radiation, these mice showed significantly reduced skin inflammation compared to normal mice in the first few hours after exposure. The modified mice also exhibited less thickening of the epidermis - a typical response to UV damage where skin cells multiply to replace damaged ones.

"We found that the first thing the cells respond to after being exposed to UV radiation is damage to the RNA, and that this is what triggers cell death and inflammation of the skin," says Simon Bekker-Jensen, a professor from Copenhagen's Cellular and Molecular Medicine department. "When we removed the ZAK gene, these responses disappeared, which means that ZAK plays a key role in the skin's response to UV-induced damage."

The research team also examined human skin cells in laboratory conditions. They found that UV exposure activated two distinct cell death pathways through ZAKα: apoptosis (controlled cell death) and pyroptosis (inflammatory cell death). Importantly, blocking ZAKα activity protected cells from both forms of death, while blocking DNA damage responses had minimal effect on immediate cell survival.

This discovery represents what Vind calls "quite the paradigm shift" in our understanding of how skin responds to UV damage. The RNA-based response appears to be faster and more effective at protecting skin from further damage than previously understood DNA damage pathways.

"Understanding how our skin responds at the cellular level to UV damage opens the door to innovative treatments for certain chronic skin conditions," notes co-author Dr. Franklin Zhong from NTU's Lee Kong Chian School of Medicine.

The research also revealed an elegant negative feedback mechanism: after activation, ZAKα triggers its own destruction, which helps limit the inflammatory response. This self-regulating system prevents excessive inflammation while allowing enough of a response to deal with the initial damage.

"This new knowledge turns things upside down," Bekker-Jensen concludes, "Now we need to rewrite the textbooks, and it will affect future research on the effects of UV radiation on the skin."

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