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Peer-reviewedCC BYNature Communications

Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response

  • Anne-Sophie M. C. Marques1,2
  • Ludwig G. Bauer1,2
  • Tuan‐Anh Nguyen3
  • Alejandro Gonzalez Orta1,2
  • Jan L. Venne1,2
  • Carol Cheng1,2
  • Esra Balıkçı1,2
  • Yusi Liu1,2
  • Barr Tivon4
  • Alena Kroupova5
  • Alessio Ciulli5
  • Nir London4
2 more authors
  • Stefan Kubicek6
  • K. Huber7,8
8 affiliations
  1. 1Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
  2. 2Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK
  3. 3CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  4. 4Department of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, Israel
  5. 5Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, 1 James Lindsay Place, DD1 5JJ, Dundee, UK
  6. 6CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [email protected]
  7. 7Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK. [email protected]
  8. 8Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, UK. [email protected]
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Abstract

6-Thioguanine (6-TG) is an FDA-approved antimetabolite drug that is widely used clinically, including for the treatment of leukemia. Its cellular effects require metabolic activation and are regulated through interactions with various proteins such as NUDT15, which catalyzes the hydrolysis of the active 6-TG metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP. Recent genome-wide CRISPR loss-of-function studies have identified another NUDIX hydrolase, NUDT5, as a crucial mediator of 6-TG toxicity. Here, we develop and validate a selective, cell-active NUDT5 degrader toolkit and orthogonally characterize target engagement, ternary complex formation, degradation kinetics, and proteome-wide selectivity. These degraders, in conjunction with orthogonal CRISPR knock-out and reconstitution experiments, support a non-enzymatic role for NUDT5 in modulating the cellular response to 6-TG. Depletion of NUDT5 protein is antagonistic to NUDT15 inhibition, suggesting a distinct mode-of-action with potential implications for patient therapy.

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Cite

BibTeXRIS
BibTeX
@article{marques2026targeted,
  title = {{Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response}},
  author = {Anne-Sophie M. C. Marques and Ludwig G. Bauer and Tuan‐Anh Nguyen and Alejandro Gonzalez Orta and Jan L. Venne and Carol Cheng and Esra Balıkçı and Yusi Liu and Barr Tivon and Alena Kroupova and Alessio Ciulli and Nir London and Stefan Kubicek and K. Huber},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74489-9},
  url = {https://doi.org/10.1038/s41467-026-74489-9},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response
AU  - Anne-Sophie M. C. Marques
AU  - Ludwig G. Bauer
AU  - Tuan‐Anh Nguyen
AU  - Alejandro Gonzalez Orta
AU  - Jan L. Venne
AU  - Carol Cheng
AU  - Esra Balıkçı
AU  - Yusi Liu
AU  - Barr Tivon
AU  - Alena Kroupova
AU  - Alessio Ciulli
AU  - Nir London
AU  - Stefan Kubicek
AU  - K. Huber
PY  - 2026
DA  - 2026/06/30
JO  - Nature Communications
DO  - 10.1038/s41467-026-74489-9
UR  - https://doi.org/10.1038/s41467-026-74489-9
AB  - 6-Thioguanine (6-TG) is an FDA-approved antimetabolite drug that is widely used clinically, including for the treatment of leukemia. Its cellular effects require metabolic activation and are regulated through interactions with various proteins such as NUDT15, which catalyzes the hydrolysis of the active 6-TG metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP. Recent genome-wide CRISPR loss-of-function studies have identified another NUDIX hydrolase, NUDT5, as a crucial mediator of 6-TG toxicity. Here, we develop and validate a selective, cell-active NUDT5 degrader toolkit and orthogonally characterize target engagement, ternary complex formation, degradation kinetics, and proteome-wide selectivity. These degraders, in conjunction with orthogonal CRISPR knock-out and reconstitution experiments, support a non-enzymatic role for NUDT5 in modulating the cellular response to 6-TG. Depletion of NUDT5 protein is antagonistic to NUDT15 inhibition, suggesting a distinct mode-of-action with potential implications for patient therapy.
SN  - 2041-1723
ER  -