New Study Reveals Mechanism for Repairing DNA Damage Linked to Cancer

Researchers at the University of Oxford and Nanyang Technological University, Singapore (NTU Singapore) have made a significant breakthrough in understanding how cells repair a particularly harmful form of DNA damage known as DNA-protein crosslinks (DPCs). This mechanism, detailed in a study published in the journal *Nucleic Acids Research* on July 21, 2025, is crucial for preventing diseases such as cancer, neurodegeneration, and promoting healthy aging.

DNA-protein crosslinks arise when unwanted proteins bind to DNA, obstructing the cell's ability to replicate its genetic material. These lesions can occur naturally during cellular metabolism or as a result of exposure to environmental agents, including chemotherapy drugs, ultraviolet (UV) radiation, and formaldehyde, the latter being a known carcinogen often found in household products and air pollution.

The research team, led by Professor Kristijan Ramadan, Toh Kian Chui Distinguished Professor in Cancer and Stem Cell Biology at NTU Singapore, identified a key repair enzyme named SPRTN, which plays a vital role in degrading these toxic attachments. The study highlights a newly discovered region within the SPRTN enzyme that significantly enhances its ability to target DPCs by recognizing chains of ubiquitin—molecules that tag proteins for degradation. This recognition increases SPRTN's repair activity by an astonishing 67-fold, allowing for the rapid clearance of DPCs without harming other vital proteins in the cell.

"In the absence of ubiquitin chains on DPCs, SPRTN operates slowly, taking hours to repair the damage. However, when ubiquitin tags are present, SPRTN's efficiency greatly improves, enabling swift action necessary for DNA repair," explained Professor Ramadan, who also serves as the Director of the Cancer Discovery and Regenerative Medicine Programme at NTU Singapore's Lee Kong Chian School of Medicine.

The implications of this research are profound. Mutations in the SPRTN gene have been linked to Ruijs-Aalfs syndrome (RJALS), a rare disorder characterized by chromosomal instability and a heightened risk of early-onset liver cancer. By understanding how SPRTN recognizes and repairs DPCs, scientists may develop strategies to bolster cellular defenses against aging-related diseases and mitigate the adverse effects of cancer therapies that induce DNA damage.

Dr. Wei Song, the study's first author and a postdoctoral researcher at Oxford, emphasized the importance of this discovery: "Our findings lay the groundwork for potential therapeutic interventions aimed at enhancing the body's natural repair mechanisms against age-related diseases and reducing chemotherapy side effects."

In an independent analysis, Dr. Jens Samol, Senior Consultant in Medical Oncology at Tan Tock Seng Hospital, Singapore, underscored the significance of the research, stating that the identification of ubiquitin chains as the primary signal for SPRTN’s activation could pave the way for novel therapeutic options. He suggested that further investigation into anti-ubiquitin antibodies or ubiquitin-proteasome inhibitors, such as bortezomib, could be beneficial in overcoming resistance to chemotherapy in some cancer patients.

Looking ahead, the research team plans to conduct additional studies utilizing zebrafish and mouse models, as well as human tissue samples, to validate their findings and explore the potential for enhancing DPC repair mechanisms. This research could revolutionize the understanding of aging and cancer, opening new avenues for therapeutic interventions that improve patient outcomes in these critical areas of health.

The study represents a critical step forward in molecular biology, shedding light on a previously obscure aspect of cellular repair mechanisms. As the global population ages and cancer remains a leading cause of mortality, understanding and enhancing DNA repair processes will be essential for developing effective treatments and interventions aimed at improving healthspan and lifespan for individuals worldwide.