A study published in Science reveals how a single protein helps cells decide when to produce the building blocks of DNA — a discovery with potential implications for treatments of cancer and inherited metabolic disorders
SOURCE: CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences
November 7, 2025
Inside every cell, a finely tuned metabolic network determines when to build, recycle, or stop producing essential molecules. A central part of this network is folate metabolism, which provides vital chemical units for the synthesis of DNA, RNA and amino acids. When this system is disturbed - through genetic mutations or a lack of dietary folates - the consequences can range from developmental disorders to cancer.
Now, researchers from CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences, together with collaborators from the University of Oxford and contributors from The Research Institute of the McGill University Health Centre (The Institute), have identified an unexpected player in this metabolic balance: the enzyme NUDT5. The study, published in Science, shows that NUDT5 helps switch off purine production—the pathway that generates the building blocks of DNA—but does so without using its enzymatic activity. Instead, the protein acts as a kind of molecular scaffold that physically restrains a key biosynthetic step when purine levels are already high.
"We were delighted to play a role in this important work, by providing cultured cells from patients with mutations in the MTHFD1 gene," said David Rosenblatt, MD, one of the study's co-authors and a Scientist in the Child Health and Human Development Program at The Institute. "Cells from patients with a genetic disease, which we originally described in 2011, were critical in showing that adenosine can also be toxic depending on the exact nature of the MTHFD1 mutation."
A new role for an old enzyme
Purines are essential molecules that cells use to build DNA and RNA and to store energy. They can be recycled from existing material, or produced from scratch through the so-called de novo pathway - an energy-intensive process that must be tightly controlled.
In their study, the researchers explored this control mechanism by studying cells with mutations in the gene MTHFD1, a crucial enzyme in the folate cycle. Folate metabolism provides the one-carbon units required for purine synthesis, and defects in this pathway cause rare genetic diseases and influence cancer risk.
Using a combination of genetic screening, metabolomics, and chemical biology, the team discovered that the protein NUDT5 interacts with another enzyme, PPAT, which catalyzes the first step of purine synthesis. When purine levels rise, NUDT5 binds to PPAT and likely locks it into an inactive form - effectively telling the cell to stop producing more purines.
Surprisingly, this function of NUDT5 does not rely on its known enzymatic activity, which breaks down nucleotide derivatives. Even when its catalytic site was chemically blocked or genetically disabled, the protein continued to regulate purine synthesis. Only when NUDT5 was completely removed - either through genetic knockout or a newly developed molecule that selectively degrades it - did cells lose this control mechanism.
Metabolic control with medical implications
The discovery sheds new light on how cells sense and respond to changes in their metabolic environment. "NUDT5 has long been classified as an enzyme that hydrolyzes metabolites," says Stefan Kubicek, Principal Investigator at CeMM and senior author of the study. "But our work reveals a completely different role - it acts as a structural regulator that determines whether the cell keeps producing purines or not."
This mechanism may also explain why some cells become resistant to certain cancer drugs. "Many chemotherapies, such as 6-thioguanine, work by mimicking purine molecules and blocking DNA synthesis", explains Tuan-Anh Nguyen, co-first author of the study. "But we found that cells without functional NUDT5–PPAT interaction were less sensitive to these treatments, suggesting that mutations in NUDT5 could contribute to drug resistance in tumors." The key role of NUDT5 in controlling cancer drug sensitivity is also supported by similar findings from Ralph DeBerardinis' laboratory that are also published in the same issue of Science.
"Our findings highlight that enzymes not only can act via the chemical reactions they catalyze, but also through their structure," concludes Kubicek. "Sometimes, it's the physical presence of a protein that makes the crucial difference."
About the study
The paper "A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis" was written by Tuan-Anh Nguyen, Jung-Ming G. Lin, Anne-Sophie M. C. Marques, Maximilian Fottner, Ludwig G. Bauer, Andreas Reicher, Diana Daum, Lorenzo Scrofani, Yusi Liu, Carol Cheng, Luna D'Angelo, Juan Sanchez, Christoph Bueschl, Nara Marella, Pisanu Buphamalai, Florian Traversi, Maša Bereš, Herwig P. Moll, Marton Siklos, Jakob-Wendelin Genger, Gerald Hofstaetter, Ludovica Villanti, Monika Malik, Christoph Klimek, Kathrin Runggatscher, Bettina Guertl, Jesper S. Hansen, Sarah Dobner, Olga Babosova, Tina Becirovic, Laura P. M. H. de Rooij, Emilio Casanova, Anna Koren, D. Sean Froese, David S. Rosenblatt, Kristaps Klavins, Andreas Bergthaler, Jörg Menche, J. Thomas Hannich, Miriam Abele, Sara Sdelci, Kathrin Lang, Kilian V. M. Huber and Stefan Kubicek. It was published in Science on 6 November 2025.
Dr. Rosenblatt's work at The Institute was supported by The Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone and by the Canadian Institutes for Health Research.
Media contacts
Wolfgang Däuble, Media Relations Manager, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. wdaeuble@cemm.at
Fabienne Landry, Media Relations, The Institute. Fabienne.landry@muhc.mcgill.ca
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