Ultraviolet (UV) rays from sunlight pose a significant threat to human health by causing DNA damage, which can lead to skin aging and cancer. Fortunately, the human body is equipped with a highly efficient repair system capable of swiftly identifying and repairing damaged DNA sites among approximately 3 billion base pairs. Recent research conducted by a team at UNIST has unveiled new insights into how this repair process operates at the molecular level.
A team of researchers, led by Professor Ja Yil Lee from the Department of Biological Sciences at UNIST, has discovered that two key proteins involved in nucleotide excision repair (NER) work together as a complex to locate UV-induced DNA lesions. This finding challenges the previously understood sequential transfer model.
Understanding Nucleotide Excision Repair
NER is a critical pathway that removes cyclobutane pyrimidine dimers (CPDs), a common form of UV-induced damage. Given the vast number of DNA base pairs, the speed and efficiency of damage detection are vital. Traditionally, the XPC protein has been known to detect structural distortions in DNA. However, because CPDs cause minimal distortion, XPC alone struggles to recognize these lesions. Instead, the UV-DDB protein is known to facilitate damage recognition.
Previously, it was believed that UV-DDB first binds to the damaged site and then hands it over to XPC in a sequential manner. However, this new study demonstrates that UV-DDB and XPC form a stable complex, referred to as the UX-complex, which cooperatively searches for damage along the DNA. Notably, XPC enhances UV-DDB’s binding affinity and search efficiency for damaged DNA.
Breakthrough Observations and Techniques
The research findings were supported by experiments utilizing single-molecule DNA curtain imaging—a technique that visualizes individual protein-DNA interactions. The researchers observed that when UV-DDB and XPC form a complex, UV-DDB binds more effectively to DNA and moves along the strand in a sliding manner, efficiently locating damage sites.
“This is the first direct observation of molecular dynamics where damage sites are precisely targeted by these proteins working together,” stated Soyeong An, the study’s first author.
Professor Lee further explained, “We uncovered that UV-DDB and XPC cooperate more closely than previously thought, accelerating the DNA repair process.” He noted that this discovery challenges the traditional textbook understanding of NER mechanisms and could have significant implications for preventing and treating UV-induced skin damage, aging, xeroderma pigmentosum, and skin cancers.
Implications for Genetic Disorders and Cancer Prevention
Meanwhile, xeroderma pigmentosum (XP) is a rare genetic disorder caused by mutations in the XPC gene, leading to a dramatically increased risk of skin cancer—sometimes hundreds to thousands of times higher than in the general population. This new understanding of the UX-complex could pave the way for novel therapeutic approaches in managing such conditions.
This research was supported by the National Research Foundation of Korea (NRF) through the Mid-Career Researcher Program and the Bio-Medical Technology Development Program. The findings were published online in the esteemed journal Nucleic Acids Research, which boasts an impact factor of 16.6, on June 18, 2025.
Journal Reference: Soyeong An, Masayuki Kusakabe, Hyun-Suk Kim, et al., “XPC-RAD23B enhances UV-DDB binding to DNA to facilitate lesion search in nucleotide excision repair,” Nucleic Acids Res. (2025).
The announcement of this discovery comes as a significant advancement in the field of molecular biology and DNA repair. As researchers continue to explore the intricacies of DNA repair mechanisms, the potential for developing targeted therapies to combat UV-induced damage and related disorders remains promising.
