RNA Damage, Not DNA, Drives Sunburn and Skin Inflammation

New research conducted at the University of Copenhagen and Nanyang Technological University (NTU) in Singapore has upended conventional wisdom about sunburn. While DNA damage has long been considered the primary cause of sunburn's harmful effects, the study reveals that RNA damage plays a critical role in the skin’s immediate response to ultraviolet (UV) radiation.

The study and its findings

Published in Molecular Cell, the study titled The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo examines how UV radiation affects skin at the cellular level. Researchers worked with both mouse models and human skin cells, identifying a similar response to UV radiation across both systems.

The team discovered that UV radiation primarily damages messenger RNA (mRNA), a molecule responsible for carrying genetic instructions from DNA to ribosomes, where proteins are synthesized. Unlike DNA, which stores genetic information long-term, RNA is a transient molecule. The researchers found that RNA damage triggers a swift cellular response known as the ribotoxic stress response, orchestrated by a protein called ZAK-alpha. This process leads to cell death and inflammation, the hallmark symptoms of sunburn.

“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.”

Dr. Anna Constance Vind.

The ribotoxic stress response

The ribotoxic stress response acts as a surveillance mechanism, detecting RNA damage and initiating inflammatory signaling. This response recruits immune cells to the site of UV exposure, leading to skin inflammation and, eventually, the death of damaged cells. Importantly, when the ZAK gene was removed in mice, these inflammatory and cell death responses were absent, underscoring ZAK-alpha’s critical role in the process.

“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.”

Dr. Anna Constance Vind.

Implications for skin defense

This discovery represents a significant shift in understanding how the skin responds to UV damage. It suggests that RNA damage, not DNA damage, initiates the skin's immediate protective response. This faster and more efficient mechanism allows the skin to address damage before it worsens.

“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.”

Dr. Simon Bekker-Jensen.

The researchers also noted that the findings could have implications for conditions beyond sunburn. Many inflammatory skin diseases worsen with sun exposure, and understanding RNA damage's role in these processes could guide the development of innovative treatments.

Reference: Vind AC, Wu Z, Firdaus MJ, et al. The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo. Mol Cell. 2024;84(24):4774-4789.e9. doi: 10.1016/j.molcel.2024.10.044

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