Rewriting Textbooks: RNA, Not DNA, Is the True Culprit Behind Sunburns

New research reveals that sunburn’s acute effects, like inflammation and cell death, are triggered by RNA damage rather than DNA damage. This discovery reshapes our understanding of the skin’s defense against UV radiation and opens doors to innovative treatments for sun-related skin conditions.

We’ve all heard the advice: avoid direct sunlight between 12 noon and 3 p.m., stay in the shade, and wear sunscreen and a hat. Yet, despite these precautions, most of us have experienced sunburn at least once. The telltale signs are familiar—reddened skin, irritation, and the urgent need for cooling relief.

You might also have been told that sunburn damages DNA. While this is true to an extent, it’s not the full story, according to a new study conducted by researchers from the University of Copenhagen and Nanyang Technological University (NTU) in Singapore.

“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,” says Assistant Professor Anna Constance Vind from the Department of Cellular and Molecular Medicine, who is one of the researchers responsible for the new study.

The study was recently published in the journal Molecular Cell.

RNA is similar to DNA, but whereas DNA is long-lived, RNA is a more transient molecule. A type of RNA, known as messenger RNA (mRNA), functions as the intermediate ‘messenger’ that carries information from DNA to make proteins – the basic building blocks of cellular components.

“DNA damage is serious as the mutations will get passed down to progenies of the cells, RNA damage happens all the time and does not cause permanent mutations. Therefore, we used to believe that the RNA is less important, as long as the DNA is intact. But in fact, damages to the RNA are the first to trigger a response to UV radiation,” Anna Constance Vind explains.

The new study was conducted on mice as well as human skin cells, and the objective was to describe the impact of UV radiation on the skin and what causes these damages. The researchers found the same skin response to UV radiation exists in both mice and human cells.

A built-in surveillance system for RNA damage

mRNA damage triggers a response in ribosomes (protein complexes that “read” the mRNA to synthesize protein), orchestrated by a protein known as ZAK-alpha – the so-called ribotoxic stress response – the new study shows. The response can be described as a surveillance system within the cells, which registers the RNA damage, leading to inflammatory signaling and recruitment of immune cells, which then leads to inflammation of the skin.

“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. In mice exposed to UV radiation we found responses such as inflammation and cell death, but 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,” says Professor Simon Bekker-Jensen from the Department of Cellular and Molecular Medicine, who is one of the other researchers responsible for the study. He adds:

“So you could say that everything depends on this one response, which monitors all protein translations occurring. The cells respond to the RNA damage, realizing that something is wrong, and this is what leads to cell death.”

Faster and more effective response

The result of the study changes our understanding of sunburn and the skin’s defense mechanisms: that RNA damage triggers a faster and more effective response, protecting the skin from further damage.

“The fact that the DNA does not control the skin’s initial response to UV radiation, but that something else does and that it does so more effectively and more quickly, is quite the paradigm shift,” says Anna Constance Vind.

We need to understand the function of RNA damage, as it may in the long term change our entire approach to prevention and treatment of sunburn.

“Many inflammatory skin diseases are worsened by sun exposure. Thus, understanding how our skin responds at the cellular level to UV damage opens the door to innovative treatments for certain chronic skin conditions,” says co-author Dr Franklin Zhong, Nanyang Assistant Professor at NTU’s Lee Kong Chian School of Medicine.

“This new knowledge turns things upside down. I think most people associate sunburn with DNA damage; it is established knowledge. But now we need to rewrite the textbooks, and it will affect future research on the effects of UV radiation on the skin,” Simon Bekker-Jensen concludes.

Reference: “The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo” by Anna Constance Vind, Zhenzhen Wu, Muhammad Jasrie Firdaus, Goda Snieckute, Gee Ann Toh, Malin Jessen, José Francisco Martínez, Peter Haahr, Thomas Levin Andersen, Melanie Blasius, Li Fang Koh, Nina Loeth Maartensson, John E.A. Common, Mads Gyrd-Hansen, Franklin L. Zhong and Simon Bekker-Jensen, 25 November 2024, Molecular Cell.
DOI: 10.1016/j.molcel.2024.10.044

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