Very excited to share the published version of our #uridine #CRISPR screen in naturemetabolism.bsky.social! 🎉
Led by Abigail Strefeler with @pagliarini-lab.bsky.social @zakbaker.bsky.social and team!
#NUDT5 #DMQ @dib-unil.bsky.social @fbm-unil.bsky.social
🔗 www.nature.com/articles/s42...
🧵1/17
Led by Abigail Strefeler with @pagliarini-lab.bsky.social @zakbaker.bsky.social and team!
#NUDT5 #DMQ @dib-unil.bsky.social @fbm-unil.bsky.social
🔗 www.nature.com/articles/s42...
🧵1/17
Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis - Nature Metabolism
A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interact...
www.nature.com
November 13, 2025 at 10:19 AM
Very excited to share the published version of our #uridine #CRISPR screen in naturemetabolism.bsky.social! 🎉
Led by Abigail Strefeler with @pagliarini-lab.bsky.social @zakbaker.bsky.social and team!
#NUDT5 #DMQ @dib-unil.bsky.social @fbm-unil.bsky.social
🔗 www.nature.com/articles/s42...
🧵1/17
Led by Abigail Strefeler with @pagliarini-lab.bsky.social @zakbaker.bsky.social and team!
#NUDT5 #DMQ @dib-unil.bsky.social @fbm-unil.bsky.social
🔗 www.nature.com/articles/s42...
🧵1/17
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/...
www.science.org/doi/10.1126/...
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 ...
www.science.org
November 6, 2025 at 7:01 PM
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/...
www.science.org/doi/10.1126/...
1/ The toolkit behind the discovery is out.
In @natcomms.nature.com, we report the selective NUDT5 degrader toolkit that helped uncover NUDT5’s hidden biology - and show antagonistic roles for NUDT5 and NUDT15 in 6-TG response. doi.org/10.1038/s414...
In @natcomms.nature.com, we report the selective NUDT5 degrader toolkit that helped uncover NUDT5’s hidden biology - and show antagonistic roles for NUDT5 and NUDT15 in 6-TG response. doi.org/10.1038/s414...
Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response - Nature Communications
Thiopurines are widely used drugs whose activity depends on cellular metabolism. Here, the authors develop chemical tools to remove NUDT5 and show that protein loss, but not inhibition, alters drug re...
doi.org
August 12, 2026 at 2:03 PM
1/ The toolkit behind the discovery is out.
In @natcomms.nature.com, we report the selective NUDT5 degrader toolkit that helped uncover NUDT5’s hidden biology - and show antagonistic roles for NUDT5 and NUDT15 in 6-TG response. doi.org/10.1038/s414...
In @natcomms.nature.com, we report the selective NUDT5 degrader toolkit that helped uncover NUDT5’s hidden biology - and show antagonistic roles for NUDT5 and NUDT15 in 6-TG response. doi.org/10.1038/s414...
Rich collections of papers on #mitochondrialdisease from the last 2 weeks! 📚
biomed.news/bims-mitdis/...
biomed.news/bims-mitdis/...
@biomednews.bsky.social @mitoscientist.bsky.social
@gavinmcstay.bsky.social
Demethoxy-CoQ and NUDT5 in nucleotide synthesis
www.nature.com/articles/s42...
biomed.news/bims-mitdis/...
biomed.news/bims-mitdis/...
@biomednews.bsky.social @mitoscientist.bsky.social
@gavinmcstay.bsky.social
Demethoxy-CoQ and NUDT5 in nucleotide synthesis
www.nature.com/articles/s42...
Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis - Nature Metabolism
A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interact...
www.nature.com
November 23, 2025 at 11:59 AM
Rich collections of papers on #mitochondrialdisease from the last 2 weeks! 📚
biomed.news/bims-mitdis/...
biomed.news/bims-mitdis/...
@biomednews.bsky.social @mitoscientist.bsky.social
@gavinmcstay.bsky.social
Demethoxy-CoQ and NUDT5 in nucleotide synthesis
www.nature.com/articles/s42...
biomed.news/bims-mitdis/...
biomed.news/bims-mitdis/...
@biomednews.bsky.social @mitoscientist.bsky.social
@gavinmcstay.bsky.social
Demethoxy-CoQ and NUDT5 in nucleotide synthesis
www.nature.com/articles/s42...
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.
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/...
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/...
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...
www.science.org
November 6, 2025 at 8:33 PM
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.
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT | Science www.science.org/doi/10.1126/...
Great work from @rjdlab.bsky.social !!
Great work from @rjdlab.bsky.social !!
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 ...
www.science.org
November 7, 2025 at 7:35 AM
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT | Science www.science.org/doi/10.1126/...
Great work from @rjdlab.bsky.social !!
Great work from @rjdlab.bsky.social !!
Thrilled to share our latest research published in @jclinical-invest.bsky.social! Our findings indicate NUDT5 is a key regulator of thiopurine metabolism, offering new insights into drug processing mechanisms.
JCI -
The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity
www.jci.org
July 16, 2025 at 10:20 PM
Thrilled to share our latest research published in @jclinical-invest.bsky.social! Our findings indicate NUDT5 is a key regulator of thiopurine metabolism, offering new insights into drug processing mechanisms.
Out now in @natmetabolism.nature.com by @jourdainlab.bsky.social 📢
A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interaction with PPAT.
A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interaction with PPAT.
Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis - Nature Metabolism
A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interact...
doi.org
November 13, 2025 at 2:10 PM
Out now in @natmetabolism.nature.com by @jourdainlab.bsky.social 📢
A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interaction with PPAT.
A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interaction with PPAT.
8/NUDT5’s involvement was surprising. R5P provides the pentose for purines, but Zheng had shown that mitochondrial suppression massively increases R5P abundance by activating the pentose phosphate pathway. He thought NUDT5 might have a different role.
November 6, 2025 at 7:04 PM
8/NUDT5’s involvement was surprising. R5P provides the pentose for purines, but Zheng had shown that mitochondrial suppression massively increases R5P abundance by activating the pentose phosphate pathway. He thought NUDT5 might have a different role.
14/When purines are abundant, the purinosome disassembles, but this requires NUDT5-PPAT binding. So NUDT5 controls both the biochemistry and cell biology of DNPB initiation.
November 6, 2025 at 7:07 PM
14/When purines are abundant, the purinosome disassembles, but this requires NUDT5-PPAT binding. So NUDT5 controls both the biochemistry and cell biology of DNPB initiation.
When purine-nucleotide levels are low, PPAT remains active, enabling cells to produce more nucleotides. But when these levels rise, the nucleotides themselves drive assembly of the PPAT–NUDT5 complex, inhibiting PPAT and shutting down further production.'
Nucleotides act as ‘molecular glue’ and can sense their own abundance
Some nucleotides have been shown to control metabolism by ‘gluing’ proteins together. Could other small molecules made naturally by cells have similar capabilities?
www.nature.com
July 17, 2026 at 3:25 AM
When purine-nucleotide levels are low, PPAT remains active, enabling cells to produce more nucleotides. But when these levels rise, the nucleotides themselves drive assembly of the PPAT–NUDT5 complex, inhibiting PPAT and shutting down further production.'
11/The NUDT5-PPAT complex seems to hold PPAT into an inactive oligomer (likely a tetramer) that suppresses DNPB. In vitro, NUDT5 reduces PPAT enzymatic activity, much better than purine nucleotides alone. But this requires that NUDT5 associate with PPAT.
November 6, 2025 at 7:05 PM
11/The NUDT5-PPAT complex seems to hold PPAT into an inactive oligomer (likely a tetramer) that suppresses DNPB. In vitro, NUDT5 reduces PPAT enzymatic activity, much better than purine nucleotides alone. But this requires that NUDT5 associate with PPAT.
Ein Enzym mit vollem Körpereinsatz - NUDT5 steuert die Produktion von DNA-Bausteinen über Struktur, nicht über Katalyse
### ACHTUNG SPERRFRIST BIS 6. NOVEMBER 2025, 20:00h MEZ###
Für ein Enzym ist es eine unerwartete Wirkungsweise: Forscher...
weiterlesen
### ACHTUNG SPERRFRIST BIS 6. NOVEMBER 2025, 20:00h MEZ###
Für ein Enzym ist es eine unerwartete Wirkungsweise: Forscher...
weiterlesen
November 6, 2025 at 7:00 PM
Ein Enzym mit vollem Körpereinsatz - NUDT5 steuert die Produktion von DNA-Bausteinen über Struktur, nicht über Katalyse
### ACHTUNG SPERRFRIST BIS 6. NOVEMBER 2025, 20:00h MEZ###
Für ein Enzym ist es eine unerwartete Wirkungsweise: Forscher...
weiterlesen
### ACHTUNG SPERRFRIST BIS 6. NOVEMBER 2025, 20:00h MEZ###
Für ein Enzym ist es eine unerwartete Wirkungsweise: Forscher...
weiterlesen
10/Mutating a single NUDT5 residue from the interface with PPAT eliminated NUDT5’s ability to bind PPAT and confer sensitivity to 6TG, both in cultured cells and xenografted tumors.
November 6, 2025 at 7:04 PM
10/Mutating a single NUDT5 residue from the interface with PPAT eliminated NUDT5’s ability to bind PPAT and confer sensitivity to 6TG, both in cultured cells and xenografted tumors.
A cell-based degrader assessment platform facilitates discovery of functional NUDT5 PROTACs https://www.biorxiv.org/content/10.1101/2025.06.13.659494v1
June 20, 2025 at 4:46 AM
A cell-based degrader assessment platform facilitates discovery of functional NUDT5 PROTACs https://www.biorxiv.org/content/10.1101/2025.06.13.659494v1
ONLINE NOW in @science.org: DeBerardinis Lab discovers protein regulating balance between purine nucleotide production pathways. 🧪
Read more ➡️ cri.utsw.edu/deberardinis...
🔖 full breakdown ⬇️
Read more ➡️ cri.utsw.edu/deberardinis...
🔖 full breakdown ⬇️
November 6, 2025 at 7:15 PM
ONLINE NOW in @science.org: DeBerardinis Lab discovers protein regulating balance between purine nucleotide production pathways. 🧪
Read more ➡️ cri.utsw.edu/deberardinis...
🔖 full breakdown ⬇️
Read more ➡️ cri.utsw.edu/deberardinis...
🔖 full breakdown ⬇️
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/...
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/...
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...
www.science.org
November 6, 2025 at 7:30 PM
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/...
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/...
9/Zheng found that NUDT5’s catalytic activity is dispensable for its ability to confer sensitivity to 6TG. Rather, he found through interactome databases and computational analysis of coevolutionary signals that NUDT5 physically associates with PPAT.
November 6, 2025 at 7:04 PM
9/Zheng found that NUDT5’s catalytic activity is dispensable for its ability to confer sensitivity to 6TG. Rather, he found through interactome databases and computational analysis of coevolutionary signals that NUDT5 physically associates with PPAT.
🧬 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
👉 link.europa.eu/cPWFVY
#HorizonEU @chembiohub.bsky.social
December 12, 2025 at 10:39 AM
🧬 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
👉 link.europa.eu/cPWFVY
#HorizonEU @chembiohub.bsky.social
3/ The toolkit allowed us to separate three different things:
blocking NUDT5 catalytic activity,
removing NUDT5 protein,
and genetically deleting or restoring NUDT5.
They do not give the same biological answer.
blocking NUDT5 catalytic activity,
removing NUDT5 protein,
and genetically deleting or restoring NUDT5.
They do not give the same biological answer.
August 12, 2026 at 2:04 PM
3/ The toolkit allowed us to separate three different things:
blocking NUDT5 catalytic activity,
removing NUDT5 protein,
and genetically deleting or restoring NUDT5.
They do not give the same biological answer.
blocking NUDT5 catalytic activity,
removing NUDT5 protein,
and genetically deleting or restoring NUDT5.
They do not give the same biological answer.
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT | Science www.science.org/doi/10.1126/...
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 ...
www.science.org
November 7, 2025 at 2:36 PM
NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT | Science www.science.org/doi/10.1126/...
19/Work from the Yang group: www.jci.org/articles/vie...
JCI -
The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity
www.jci.org
November 6, 2025 at 7:12 PM
19/Work from the Yang group: www.jci.org/articles/vie...