ICR Scientists Reveal How Key DNA Repair Enzyme Is Switched On Inside Cells

ICR Scientists Reveal How Key DNA Repair Enzyme Is Switched On Inside Cells

(IN BRIEF) Researchers at The Institute of Cancer Research, London, have uncovered how the DNA repair enzyme XPF-ERCC1 is recruited to sites of damage and activated inside cells, resolving a long-standing question in molecular biology and providing structural insights that could inform future cancer research. Using a combination of AlphaFold AI modelling and cryogenic electron microscopy, the team mapped how the regulatory protein SLX4 binds to and activates XPF-ERCC1, explaining how the enzyme remains inactive under normal conditions but becomes switched on when DNA repair is needed. The study, published in Nature Communications and funded mainly by the ICR with support from the Medical Research Council, highlights how tightly controlled DNA repair is essential for genome integrity while also showing how cancer cells may exploit these pathways. Senior author Dr Basil Greber noted that while the work is fundamental, it lays the groundwork for future strategies to selectively manipulate DNA repair in cancer cells and potentially improve existing therapies.

(PRESS RELEASE) LONDON, 5-Feb-2026 — /EuropaWire/ — Scientists at The Institute of Cancer Research, London, have revealed new molecular insights into how a critical DNA repair enzyme is recruited and activated inside cells, providing a clearer understanding of how cells maintain genome stability and opening potential avenues for refining cancer treatments in the future.

The study focused on the enzyme XPF-ERCC1, a key player in multiple DNA repair pathways that protects cells from genetic damage. While its importance in repairing damaged DNA has long been recognised, researchers had not previously been able to fully explain how the enzyme is directed to specific sites of damage or how its activity is precisely regulated once there.

Image: Rendering of the XPF-ERCC1 enzyme complex provided by Dr Basil Greber (XPF in cyan, ERCC1 in blue, SLX4 in orange, SLX4IP in yellow, with DNA wrapped around nucleosomes in the background)

Cells are constantly exposed to sources of DNA damage, ranging from normal metabolic processes to environmental stressors. To survive, they rely on tightly controlled repair mechanisms that detect and correct DNA lesions before they lead to harmful mutations or cell death. XPF-ERCC1 plays a central role in this process by recognising structural distortions in DNA rather than specific sequences, allowing it to act wherever repair is needed.

However, this ability also makes XPF-ERCC1 potentially dangerous if activated at the wrong time or place, as it could create unnecessary DNA breaks. To prevent this, its activity must be carefully regulated by other proteins. One of these regulators is SLX4, which not only guides XPF-ERCC1 to sites of damage but also stimulates its cutting activity once it arrives. Until now, the precise mechanism by which SLX4 controls XPF-ERCC1 remained unclear.

To address this, the research team used a combination of advanced computational and imaging techniques. They integrated AlphaFold, an AI system capable of predicting protein structures from amino acid sequences, with high-resolution cryogenic electron microscopy, which produces detailed three-dimensional images of biological molecules at near-atomic resolution.

This approach enabled the scientists to identify exact docking sites where SLX4 binds to XPF-ERCC1 and to observe how these interactions change in the presence of damaged DNA. By mapping these structural relationships, they were able to visualise the enzyme in its active form and clarify how molecular switches regulate its function. These findings explain how XPF-ERCC1 remains inactive under normal conditions but becomes activated precisely when and where DNA repair is required.

The research, published in Nature Communications, was primarily funded by the Institute of Cancer Research, with additional support from the Medical Research Council.

While DNA repair is essential for healthy cells, cancer cells can exploit these same pathways to survive chemotherapy and radiotherapy. The study therefore provides an important foundation for future work aimed at selectively disrupting DNA repair mechanisms in cancer cells.

Dr Basil Greber, Senior Author and Group Leader of the Structural Biology of DNA Repair Complexes Group at the ICR, emphasised that the findings represent a fundamental scientific advance rather than an immediate clinical breakthrough. He noted that a deeper understanding of DNA repair enzymes is crucial for developing more precise strategies to weaken cancer cells’ ability to repair their genomes, which could ultimately enhance the effectiveness of existing treatments.

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SOURCE: Institute of Cancer Research