Project news Cellular 'handbrake' controls cancer drug response, study shows

🧬 Scientists from IMI project EUbOPEN have worked out how an enzyme called NUDT5 acts as a handbrake on the production of a building block of DNA. The finding, published in @science.org, explains why some cancers are resistant to treatment.
👉 link.europa.eu/cPWFVY
#HorizonEU @chembiohub.bsky.social

Thanks for highlighting our work and for the support from EUbOPEN and IHI. This was very much a team effort, made possible by close collaboration across Oxford, Vienna, and our partners - and by the public-private framework that lets discovery science translate into impact.

Congratulations to co-first authors Mira & Ani and teams at @cmd.ox.ac.uk @ndm.ox.ac.uk, @promegacorporation.bsky.social, @stonybrooku.bsky.social
Huge thanks to our funders @myelomauk.bsky.social, Bayer, and @ihieurope.bsky.social (4/4)

Result: we can determine EC50 values in MTAP wild-type and MTAP-deleted cells, quantifying inhibitor potency in a cell-context-dependent way - adding another layer of personalised medicine. (3/4)

We investigated the PRMT5 inhibitor GSK3326595 and developed CBH-002, a BRET probe that binds a genetically encoded PRMT5-NanoLuc biosensor and senses changes in SAM/MTA. With Matt Robers & Peter Tonge, we used it to study MTA-uncompetitive inhibitors that target MTAP-deleted tumours. (2/4)

A BRET biosensor for measuring uncompetitive engagement of PRMT5 complexes in cells - Nature Communications This study presents a BRET biosensor that measures how anticancer drugs cooperatively engage PRMT5 complexes in cells, revealing how cellular metabolites such as SAM and MTA enhance drug action and en...

New in @natcomms.nature.com: a live-cell BRET biosensor to study how PRMT5 inhibitors engage their target in a tumour-context cellular environment (1/4)

Open access paper: doi.org/10.1038/s414...

Congratulations @jourdainlab.bsky.social !

Discovery reveals ‘handbrake’ that controls cancer drug response | Oxford University and Austrian researchers uncover a previously unknown ‘handbrake’ mechanism controlling how cells respond to cancer drugs, reshaping global understanding of cell metabolism and drug

www.ox.ac.uk/news/2025-11... @ox.ac.uk @medsci.ox.ac.uk

Thank you for sharing! We’re lucky to have support from @ihieurope.bsky.social and @horizoneu.bsky.social - it’s the kind of open, collaborative funding that lets discoveries like this happen here in Oxford (and beyond!).

Thank you so much, @rjdlab.bsky.social! Great to see our independent studies complement each other so beautifully and deepen the picture of purine metabolism.

Here's the beautiful paper from @chembiohub.bsky.social reporting NUDT5's role in purine synthesis. I cannot emphasize enough how gracious and open these authors were when we all realized we were working on the same mechanism.

Thank you - much appreciated!

Beautiful discovery by the Huber and Kubicek labs and a wonderful example of using targeted protein degradation to probe novel non-catalytic functions.

Thanks Jordan!

NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that ...

1/New paper from Zheng Wu, Phong Nguyen et al. @cri-utsw.bsky.social shows how cells balance the two pathways that produce purine nucleotides: de novo purine biosynthesis (DNPB) and purine salvage. The surprising mechanism involves NUDT5, a Nudix hydrolase

www.science.org/doi/10.1126/...

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 depende...

17/NUDT5 is having a moment – see excellent work from other labs reporting roles for NUDT5 in purine metabolism. These include papers by Kilian Huber and Stefan Kubicek, also out today (see link), and work by Alexis Jourdain and Jun Yang (see next posts)
www.science.org/doi/10.1126/...

JCI study underscores the role of NUDT5 in shaping patient response to thiopurines, pointing to opportunities for more individualised treatment.

www.jci.org/articles/vie...

Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis Nucleotides are essential for nucleic acid synthesis, signaling, and metabolism, and can be synthesized de novo or through salvage. Rapidly proliferating cells require large amounts of nucleotides, ma...

Link to study from @jourdainlab.bsky.social lab:

www.biorxiv.org/content/10.1...

NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT Cells generate purine nucleotides through de novo purine biosynthesis (DNPB) and purine salvage. Purine salvage represses DNPB to prevent excessive purine nucleotide synthesis through mechanisms that ...

Shout-out to complementary work from @rjdlab.bsky.social

www.science.org/doi/10.1126/...

Grateful to Stefan Kubicek & team @cemm.oeaw.ac.at for a fantastic collaboration. Big thanks also to
@ox.ac.uk
@ndm.ox.ac.uk
@cmd.ox.ac.uk
and funders
@horizoneu.bsky.social
@wellcometrust.bsky.social

🌍 Why it matters: This changes how we think about enzyme regulation, metabolism, and cancer-drug response - and shows the power of chemistry to reveal new biology.

🔬 Using proteomics, we discovered NUDT5 binds PPAT, the rate-limiting enzyme in de novo purine synthesis - a “handbrake” mechanism linking metabolism and disease.

🧪 What we did: Tested NUDT5 enzyme inhibitors (no effect) → built a selective NUDT5 degrader (dNUDT5).
Removing the protein revealed an entirely non-enzymatic scaffolding function. #gottaloveTPD

🧩 Motivation: In a CRISPR screen in a “folate trap” model, NUDT5 emerged as a rescue factor in MTHFD1-deficient cells - hinting at a deeper role in cellular metabolism.

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 depende...

New in @science.org 🧬

What if an enzyme you thought you knew turned out to control metabolism in a completely new way?

We found that NUDT5 acts as a molecular handbrake on purine synthesis, reshaping how cells make DNA building blocks and respond to cancer drugs.

www.science.org/doi/10.1126/...

Awards & Honors | Gesellschaft Deutscher Chemiker e.V.

If you have defended your PhD in Biochemistry or a related field in 2023 or have a publication in this field in 2023 (PhD less than 4 years ago), consider applying for the Förderpreis of the @gdchbiochem.bsky.social of @gdch.bsky.social.

Deadline: April 30th.

en.gdch.de/network-stru...

Jensen Huang’s comments from JPM24 are now summarized in a Nvidia blog post. He doubles down on exactly the kinds of things that I’ve been cautioning are wildly optimistic. More below. 👇🏽 1/

We have two postdoc positions available for structural biologists to help us study the function of proteins involved in RNA & ubiquitin metabolism. Deadline 9th October 2023. Links: 1) tinyurl.com/msc4vckb 2) tinyurl.com/4dukkuy6

Target deconvolution with matrix-augmented pooling strategy reveals cell-specific drug-protein inter... Target deconvolution is a crucial but costly and time-consuming task that hinders large-scale profiling for drug discovery. We present a matrix-augmen…

Excited to inaugurate our Bluesky account with this paper from our friends in the Tan lab on a matrix-augmented pooling strategy for thermal profiling - glad we could contribute! www.sciencedirect.com/science/arti...

Hello Bluesky! Please tell us why you had to hide away for sooo long!