A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis
Folate metabolism is intricately linked to purine de novo synthesis through the incorporation of folate-derived one-carbon units into the purine scaffold. By investigating chemical and genetic dependencies caused by mutations in methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1), we discovered a key role for Nudix hydrolase 5 (NUDT5) in regulating purine de novo synthesis. Genetic depletion and selective chemical degradation showed that a scaffolding role, rather than NUDT5 enzymatic activity, was causing this phenotype. NUDT5 interacted with phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme of purine de novo synthesis, to repress the pathway in response to increased purine abundance. Through this mechanism, loss of NUDT5 mediates resistance to purine analogs in cancer treatment and prevents adenosine toxicity in MTHFD1 deficiency.
Authors
- Jakob‐Wendelin Genger (ORCID: https://orcid.org/0000-0003-4502-1094)
- Florian Traversi
- D. Sean Froese (ORCID: https://orcid.org/0000-0003-1557-3517)
- Ludwig G. Bauer (ORCID: https://orcid.org/0000-0002-2235-3945)
- Miriam Abele (ORCID: https://orcid.org/0000-0003-0084-2999)
- Kristaps Klavins (ORCID: https://orcid.org/0000-0001-9577-9990)
- Marton I. Siklos
- Kathrin Runggatscher
- Jörg Menche (ORCID: https://orcid.org/0000-0002-1583-6404)
- Anna Koren (ORCID: https://orcid.org/0000-0003-2528-4970)
- David S. Rosenblatt (ORCID: https://orcid.org/0000-0002-0548-365X)
- Oľga Babošová (ORCID: https://orcid.org/0000-0001-7036-6807)
- Maximilian Fottner (ORCID: https://orcid.org/0000-0002-8628-183X)
- Sara Sdelci (ORCID: https://orcid.org/0000-0003-1330-4364)
- Christoph Klimek (ORCID: https://orcid.org/0009-0004-7036-8799)
- Emilio Casanova (ORCID: https://orcid.org/0000-0001-7992-5361)
- Andreas Reicher
- Tina Becirovic (ORCID: https://orcid.org/0009-0009-6074-2907)
- Nara Marella (ORCID: https://orcid.org/0000-0001-5254-6089)
- K. Huber (ORCID: https://orcid.org/0000-0002-1103-5300)
- Carol Cheng (ORCID: https://orcid.org/0009-0006-3165-5183)
- Anne-Sophie M. C. Marques (ORCID: https://orcid.org/0009-0005-5726-508X)
- Herwig P. Moll (ORCID: https://orcid.org/0000-0001-6438-9068)
- Andreas Bergthaler (ORCID: https://orcid.org/0000-0003-0597-1976)
- Juan Sánchez-Ávila (ORCID: https://orcid.org/0000-0002-5920-7618)
- J. Thomas Hannich (ORCID: https://orcid.org/0000-0002-2286-4956)
- Kathrin Lang (ORCID: https://orcid.org/0000-0002-1318-6567)
- Tuan‐Anh Nguyen (ORCID: https://orcid.org/0000-0001-7809-5175)
- Bettina Guertl
- Jung-Ming G. Lin (ORCID: https://orcid.org/0000-0002-3260-5544)
- Pisanu Buphamalai (ORCID: https://orcid.org/0000-0002-9024-4193)
- Stefan Kubicek (ORCID: https://orcid.org/0000-0003-0855-8343)
- Jesper S. Hansen (ORCID: https://orcid.org/0000-0003-1638-1285)
- Christoph Bueschl (ORCID: https://orcid.org/0000-0003-1729-9785)
- Laura de Rooij (ORCID: https://orcid.org/0000-0002-1810-4620)
- Ludovica Villanti
- Monika Malik (ORCID: https://orcid.org/0000-0002-4902-3620)
- Yusi Liu (ORCID: https://orcid.org/0000-0003-4953-6909)
- Sarah Dobner (ORCID: https://orcid.org/0009-0000-4186-9958)
- Maša Bereš (ORCID: https://orcid.org/0009-0008-5247-5880)
- Lorenzo Scrofani (ORCID: https://orcid.org/0009-0000-6805-8338)
- Gerald Hofstaetter (ORCID: https://orcid.org/0009-0009-4111-1763)
- Diana Daum (ORCID: https://orcid.org/0009-0007-3827-4970)
- Luna D’Angelo L.d.D. (ORCID: https://orcid.org/0009-0005-6268-3462)
Institutions
- University of Vienna (AT)
- Austrian Academy of Sciences (AT)
- University of Zurich (CH)
- Discovery Centre (CA)
- Nuffield Orthopaedic Centre (GB)
- Max Perutz Labs (AT)
- ETH Zurich (CH)
- Comprehensive Cancer Center Vienna (AT)
- CeMM Research Center for Molecular Medicine (AT)
- University Children's Hospital Zurich (CH)
- Centre for Genomic Regulation (ES)
- McGill University (CA)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Science
- Published
- 2025-11-06
- DOI
- https://doi.org/10.1126/science.adv4257
- Citations
- 3
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 2.42