Ultraviolet (UV) rays from sunlight pose a significant threat to DNA integrity, leading to skin aging and cancer. Fortunately, the human body is equipped with a sophisticated repair system capable of identifying and repairing damaged DNA among approximately 3 billion base pairs. Recent research conducted by a team at the Ulsan National Institute of Science and Technology (UNIST) has provided new insights into the molecular mechanisms of this repair process.
A research group 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) operate together as a complex to detect UV-induced DNA damage. This finding challenges the previously understood sequential transfer model.
Unveiling the Role of Nucleotide Excision Repair
NER is a critical pathway responsible for removing cyclobutane pyrimidine dimers (CPDs), a common form of UV-induced DNA damage. Given the vast number of DNA base pairs, the speed and efficiency of damage detection are crucial. Traditionally, the XPC protein was thought to detect structural distortions in DNA. However, due to the minimal distortion caused by CPDs, XPC alone struggles to recognize these lesions. 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 transfers it 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.
Innovative Techniques and Observations
The research team employed single-molecule DNA curtain imaging, a technique that visualizes individual protein-DNA interactions, to support their findings. They 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 explained, “We uncovered that UV-DDB and XPC cooperate more closely than previously thought, accelerating the DNA repair process.” He further noted, “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
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 research offers hope for better understanding and potentially mitigating the risks associated with such genetic conditions.
The study 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 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).
Looking Ahead: The Future of DNA Repair Research
This breakthrough not only advances our understanding of DNA repair mechanisms but also opens new avenues for research into preventing and treating UV-induced skin damage and related diseases. As scientists continue to explore the intricacies of DNA repair, the potential for developing targeted therapies and preventive measures grows.
As the scientific community delves deeper into the molecular dance of DNA repair proteins, the hope is to unlock further secrets that could lead to significant advancements in medical science, particularly in the fields of dermatology and oncology.
