Of acting purely as an enzyme NUDT5 seems to act like a kind of structure that holds together and organizes how cells handle their metabolism.
So the team tried that with NUDT5 expecting it to show something about drug resistance.
When NUDT5 was gone, the cells suddenly became much more resistant to the drug.
When NUDT15 is gone, cells are more likely to be hurt by the drug.
It suggests the two proteins control drug response in different ways.
Doctors have been giving 6-thioguanine (6-TG) to leukemia patients for than seventy years. It works. There has never been any doubt about that. What has remained very confusing after all this time is the detailed molecular story: why some cancer cells die because of the drug while others ignore it and live on.A new study is finally starting to solve that puzzle. The answer involved a protein that nobody thought would be important. NUDT5.The research came from a partnership between the CeMM Research Center for Molecular Medicine in Vienna the University of Oxford the Weizmann Institute of Science and the University of Dundee. It builds on a discovery published in Science in 2025, where the same Kubicek and Huber labs found something strange about NUDT5: its most important job inside the cell might not be related to the chemical reaction it is supposed to do. Of acting purely as an enzyme NUDT5 seems to act like a kind of structure that holds together and organizes how cells handle their metabolism. That unusual non-chemical role turned out to be very important when it came to 6-TG.As per Tuan-Anh Nguyen, one of the study's first authors at CeMM it was mentioned that they originally thought that NUDT5 would affect 6-TG through its enzyme activity, and instead they found that stopping the enzyme had little effect.What mattered was whether the protein was there. Moreover, that single finding changed everything the researchers thought they knew.Blocking it wasn't enough.The drugs that target a protein work by stopping its enzyme function. Turning it off basically. So the team tried that with NUDT5 expecting it to show something about drug resistance. It didn’t. The real discovery happened when they stopped trying to turn it off and instead made it go away completely using a method called targeted protein degradation.To do this, the Oxford-based team, led by the Huber lab created a set of specific molecules that could mark NUDT5 for destruction inside the cell. One of those compounds called dNUDT5 turned out to be their effective tool. As Anne-Sophie Marques, one of the papers authors mentioned that they created a cell-based platform to speed up finding NUDT5 degraders. This platform helped guide the chemical work that eventually made dNUDT5, the degrader. They also made control compounds. Molecules that could stick to NUDT5 without getting rid of it. So they could fairly compare blocking versus deleting.The results were clear. Just stopping NUDT5’s enzyme function didn’t change how the cells reacted to 6-TG much. When NUDT5 was gone, the cells suddenly became much more resistant to the drug. Additional genetic experiments supported the idea.Moreover, another researcher, Kilian Huber, from Oxford's Centre for Medicines Discovery, added that the chemical degraders let us see what a protein does as an enzyme versus what it does by being there. In this case that difference was important: taking out NUDT5 showed biology that normal inhibitors didn’t catch."A Second Protein Enters the SceneResearcher Ludwig Bauer described watching the data come in as one of the exciting parts of the project, remembering the moment it became clear that dNUDT5 was helping cells avoid 6-TG’s harmful effects in a way that increased with dose.The team also discovered a link between NUDT5 and a more familiar protein, NUDT15. A protein already known to affect how people respond to thiopurine drugs like 6-TG. Interestingly, the two proteins seem to work in ways. When NUDT15 is gone, cells are more likely to be hurt by the drug. When NUDT5 is gone, they are more likely to survive. It suggests the two proteins control drug response in different ways. They further mentioned that the results show that proteins can have roles that have nothing to do with their enzyme activity. In fact, by removing NUDT5 of just blocking it we were able to find a hidden part of biology that helps decide how cells react to a drug that has been used for years.What this means for the futureThis discovery won't create a leukemia treatment right away. It does show why patients can react so differently to the same old drug. And it supports the idea of degrading proteins instead of just stopping them since some important biology only appears when a protein is completely gone
