Breakthrough Discovery in DNA Repair Mechanism by NTU and Oxford Researchers

Researchers from the University of Oxford and Nanyang Technological University, Singapore (NTU Singapore) have made a significant advancement in understanding how cells repair a highly toxic form of DNA damage, known as DNA-protein crosslinks (DPCs). This groundbreaking study, published in the journal Nucleic Acids Research on July 22, 2025, reveals the mechanism through which the enzyme SPRTN recognizes and repairs these harmful lesions, which are implicated in cancer, neurodegeneration, and premature aging.
The research, led by Professor Kristijan Ramadan, Toh Kian Chui Distinguished Professor in Cancer and Stem Cell Biology at NTU and Honorary Senior Researcher at the Department of Oncology at the University of Oxford, identifies a specialized region within the SPRTN enzyme that enhances its ability to target DPC lesions. This discovery marks a pivotal moment in molecular biology and has profound implications for cancer therapy and the understanding of aging.
According to the study, DPCs arise from various sources, including normal cellular metabolism and environmental factors such as chemotherapy, UV radiation, and formaldehyde—a recognized Group 1 carcinogen found in numerous household products. If left unrepaired, these lesions can disrupt DNA replication, leading to severe cellular dysfunction and contributing to diseases such as cancer and neurodegeneration.
SPRTN plays an essential role in cellular defense by traveling along DNA strands and degrading the proteins that form DPCs, thereby clearing the blockage to facilitate DNA replication. Prior to this study, the specific mechanisms by which SPRTN recognized and repaired DPCs were largely unknown. The research team has now elucidated that the presence of ubiquitin chains on DPC lesions significantly enhances SPRTN's activity—by as much as 67 times—allowing for rapid and efficient repair.
"In the absence of ubiquitin chains, SPRTN is slow and inefficient, taking hours to clear DNA lesions. However, the presence of these chains triggers a rapid increase in SPRTN's activity to break down harmful protein attachments," Professor Ramadan explained. This revelation provides vital insights into the natural defenses of human cells and underscores the importance of ubiquitin as a signaling mechanism for DNA repair.
The implications of this research extend beyond fundamental biology. Dr. Wei Song, a postdoctoral researcher at Oxford and the study's first author, stated, "Understanding how our bodies repair DNA damage caused by DPCs has been a long-standing mystery. Our findings pave the way for developing potential strategies to enhance the body's defenses against age-related diseases and reduce side effects associated with cancer therapies that damage DNA."
Dr. Jens Samol, a Senior Consultant in Medical Oncology at Tan Tock Seng Hospital in Singapore, commented on the significance of the study, noting, "The identification of ubiquitin chains as the main signal for SPRTN's activation is a significant advancement. It opens up possibilities for exploring new therapeutic options, such as anti-ubiquitin antibodies or ubiquitin-proteasome inhibitors, to address chemotherapy resistance in cancer patients."
Future research by the team will include ongoing studies using zebrafish, mouse models, and human tissues to further validate their findings and explore potential therapeutic interventions. This research could ultimately revolutionize the understanding of aging processes and provide new avenues for cancer treatment.
In conclusion, the discovery of how SPRTN targets and repairs DPCs not only contributes to the understanding of cellular mechanisms but also holds promise for enhancing cancer treatment strategies and improving health outcomes in aging populations. The integration of these findings into therapeutic frameworks may significantly transform approaches to combat age-related diseases and improve the efficacy of cancer therapies.
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