Alexis A. Jourdain
@jourdainlab.bsky.social
Swiss-Belgian biologist, assistant professor @UNIL with interest in mitochondria, energy metabolism, innate immunity and systems biology.
That’s it, thanks for reading this long thread! 🙏
17/17
17/17
November 13, 2025 at 10:19 AM
That’s it, thanks for reading this long thread! 🙏
17/17
17/17
Also from last week, a Kubicek & Huber paper on MTHFD1 & NUDT5 👇
🔗 www.science.org/doi/10.1126/...
15/17
🔗 www.science.org/doi/10.1126/...
15/17
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 13, 2025 at 10:19 AM
Also from last week, a Kubicek & Huber paper on MTHFD1 & NUDT5 👇
🔗 www.science.org/doi/10.1126/...
15/17
🔗 www.science.org/doi/10.1126/...
15/17
Published last week a new paper from Ralph DeBerardinis with really cool #purinosome imaging 🧫✨
🔗 www.science.org/doi/10.1126/...
14/17
🔗 www.science.org/doi/10.1126/...
14/17
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 13, 2025 at 10:19 AM
Published last week a new paper from Ralph DeBerardinis with really cool #purinosome imaging 🧫✨
🔗 www.science.org/doi/10.1126/...
14/17
🔗 www.science.org/doi/10.1126/...
14/17
This year, a study from J. Yang links NUDT5 to thiopurine resistance in patients:
🔗 www.jci.org/articles/vie...
13/17
🔗 www.jci.org/articles/vie...
13/17
JCI -
The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity
www.jci.org
November 13, 2025 at 10:19 AM
This year, a study from J. Yang links NUDT5 to thiopurine resistance in patients:
🔗 www.jci.org/articles/vie...
13/17
🔗 www.jci.org/articles/vie...
13/17
Same year, a screen by J. Doench & D. Root also found NUDT5 loss → 6-TG resistance:
🔗 www.nature.com/articles/nbt...
12/17
🔗 www.nature.com/articles/nbt...
12/17
Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9 - Nature Biotechnology
Genome-wide sgRNA libraries based on rules for on-target activity improve results of Cas9-based screens and facilitate a further refinement of on- and off-target prediction algorithms.
www.nature.com
November 13, 2025 at 10:19 AM
Same year, a screen by J. Doench & D. Root also found NUDT5 loss → 6-TG resistance:
🔗 www.nature.com/articles/nbt...
12/17
🔗 www.nature.com/articles/nbt...
12/17
First, a 2016 screen by N. Benvenisty showed NUDT5 loss → 6-thioguanine resistance:
🔗 www.nature.com/articles/nat...
11/17
🔗 www.nature.com/articles/nat...
11/17
Derivation and differentiation of haploid human embryonic stem cells - Nature
Haploid human embryonic stem cells have been derived from haploid oocytes, the cells maintain a normal haploid karyotype as pluripotent cells and, unexpectedly, as differentiated cells — loss-of-funct...
www.nature.com
November 13, 2025 at 10:19 AM
First, a 2016 screen by N. Benvenisty showed NUDT5 loss → 6-thioguanine resistance:
🔗 www.nature.com/articles/nat...
11/17
🔗 www.nature.com/articles/nat...
11/17
After our bioRxiv upload in March, THREE related #NUDT5 preprints appeared on-line! 🤯
We kept in touch with the authors and tried our best to coordinate publication. Here are some links, also to older relevant papers:
10/17
We kept in touch with the authors and tried our best to coordinate publication. Here are some links, also to older relevant papers:
10/17
November 13, 2025 at 10:19 AM
After our bioRxiv upload in March, THREE related #NUDT5 preprints appeared on-line! 🤯
We kept in touch with the authors and tried our best to coordinate publication. Here are some links, also to older relevant papers:
10/17
We kept in touch with the authors and tried our best to coordinate publication. Here are some links, also to older relevant papers:
10/17
Our findings link fundamental nucleotide metabolism to clinical outcomes, highlighting #NUDT5 as a biomarker for predicting therapy efficacy in cancer, autoimmune, and viral diseases.
Huge thanks to all co-authors and funders! @snsf_ch
And now, some exciting related work 👇
9/17
Huge thanks to all co-authors and funders! @snsf_ch
And now, some exciting related work 👇
9/17
November 13, 2025 at 10:19 AM
Our findings link fundamental nucleotide metabolism to clinical outcomes, highlighting #NUDT5 as a biomarker for predicting therapy efficacy in cancer, autoimmune, and viral diseases.
Huge thanks to all co-authors and funders! @snsf_ch
And now, some exciting related work 👇
9/17
Huge thanks to all co-authors and funders! @snsf_ch
And now, some exciting related work 👇
9/17
This led us to propose a new mechanism ⚙️
Without NUDT5, hyperactive PPAT drains PRPP into purine synthesis, with two major consequences:
1️⃣ No PRPP left for pyrimidines synthesis
2️⃣ Nucleobase analogs can’t become toxic nucleotides 💥
8/17
Without NUDT5, hyperactive PPAT drains PRPP into purine synthesis, with two major consequences:
1️⃣ No PRPP left for pyrimidines synthesis
2️⃣ Nucleobase analogs can’t become toxic nucleotides 💥
8/17
November 13, 2025 at 10:19 AM
This led us to propose a new mechanism ⚙️
Without NUDT5, hyperactive PPAT drains PRPP into purine synthesis, with two major consequences:
1️⃣ No PRPP left for pyrimidines synthesis
2️⃣ Nucleobase analogs can’t become toxic nucleotides 💥
8/17
Without NUDT5, hyperactive PPAT drains PRPP into purine synthesis, with two major consequences:
1️⃣ No PRPP left for pyrimidines synthesis
2️⃣ Nucleobase analogs can’t become toxic nucleotides 💥
8/17
Purines & pyrimidines share PRPP, the sugar for de novo synthesis. In NUDT5-KO cells, we found that PRPP levels were low ⚠️
Also, we found these cells are resistant to both purine & pyrimidine nucleoBASE analogs, but not nucleoside analogs, hinting at a key metabolic shift.
7/17
Also, we found these cells are resistant to both purine & pyrimidine nucleoBASE analogs, but not nucleoside analogs, hinting at a key metabolic shift.
7/17
November 13, 2025 at 10:19 AM
Purines & pyrimidines share PRPP, the sugar for de novo synthesis. In NUDT5-KO cells, we found that PRPP levels were low ⚠️
Also, we found these cells are resistant to both purine & pyrimidine nucleoBASE analogs, but not nucleoside analogs, hinting at a key metabolic shift.
7/17
Also, we found these cells are resistant to both purine & pyrimidine nucleoBASE analogs, but not nucleoside analogs, hinting at a key metabolic shift.
7/17
This challenges the dogma that CoQ is required for pyrimidine synthesis! And it links to recent findings on #rhodoquinone, another CoQ-like molecule in mitochondrial electron transport.
5/17
5/17
November 13, 2025 at 10:19 AM
This challenges the dogma that CoQ is required for pyrimidine synthesis! And it links to recent findings on #rhodoquinone, another CoQ-like molecule in mitochondrial electron transport.
5/17
5/17
#COQ7 is essential for CoQ synthesis, so why wasn’t it a hit? 🤔
Using lipidomics & modeling, we propose that #demethoxy-CoQ, which builds up when COQ7 is lost, can accepts e⁻ from DHODH, but not from OXPHOS complexes, thus ensuring pyrimidine synthesis!
4/17
Using lipidomics & modeling, we propose that #demethoxy-CoQ, which builds up when COQ7 is lost, can accepts e⁻ from DHODH, but not from OXPHOS complexes, thus ensuring pyrimidine synthesis!
4/17
November 13, 2025 at 10:19 AM
#COQ7 is essential for CoQ synthesis, so why wasn’t it a hit? 🤔
Using lipidomics & modeling, we propose that #demethoxy-CoQ, which builds up when COQ7 is lost, can accepts e⁻ from DHODH, but not from OXPHOS complexes, thus ensuring pyrimidine synthesis!
4/17
Using lipidomics & modeling, we propose that #demethoxy-CoQ, which builds up when COQ7 is lost, can accepts e⁻ from DHODH, but not from OXPHOS complexes, thus ensuring pyrimidine synthesis!
4/17
Top hits were the 3 canonical pyrimidine synthesis enzymes + #CoQ genes 🧬
But two genes stood out: COQ7, conspicuous by its absence 👀, and NUDT5, the next strongest hit after the pyrimidine enzymes.
3/17
But two genes stood out: COQ7, conspicuous by its absence 👀, and NUDT5, the next strongest hit after the pyrimidine enzymes.
3/17
November 13, 2025 at 10:19 AM
Top hits were the 3 canonical pyrimidine synthesis enzymes + #CoQ genes 🧬
But two genes stood out: COQ7, conspicuous by its absence 👀, and NUDT5, the next strongest hit after the pyrimidine enzymes.
3/17
But two genes stood out: COQ7, conspicuous by its absence 👀, and NUDT5, the next strongest hit after the pyrimidine enzymes.
3/17
Genes for nucleotide synthesis are essential for cell growth, unless nucleosides for salvage are provided. This gave us an idea💡
To identify new players in pyrimidine synthesis, we ran a genome-wide CRISPR-Cas9 screen in media ± uridine, a #pyrimidine #nucleoside.
2/17
To identify new players in pyrimidine synthesis, we ran a genome-wide CRISPR-Cas9 screen in media ± uridine, a #pyrimidine #nucleoside.
2/17
November 13, 2025 at 10:19 AM
Genes for nucleotide synthesis are essential for cell growth, unless nucleosides for salvage are provided. This gave us an idea💡
To identify new players in pyrimidine synthesis, we ran a genome-wide CRISPR-Cas9 screen in media ± uridine, a #pyrimidine #nucleoside.
2/17
To identify new players in pyrimidine synthesis, we ran a genome-wide CRISPR-Cas9 screen in media ± uridine, a #pyrimidine #nucleoside.
2/17
Congrats to PhD student @marcellharhai.bsky.social , who joined the lab 2y ago (!) and led this work, to second author M. Foged, and to all our collaborators!
We are thankful to our funding sources including the @FSRMM, Novartis and @snsf.ch.
@dib-unil.bsky.social @fbm-unil.bsky.social
We are thankful to our funding sources including the @FSRMM, Novartis and @snsf.ch.
@dib-unil.bsky.social @fbm-unil.bsky.social
July 28, 2025 at 5:40 AM
Congrats to PhD student @marcellharhai.bsky.social , who joined the lab 2y ago (!) and led this work, to second author M. Foged, and to all our collaborators!
We are thankful to our funding sources including the @FSRMM, Novartis and @snsf.ch.
@dib-unil.bsky.social @fbm-unil.bsky.social
We are thankful to our funding sources including the @FSRMM, Novartis and @snsf.ch.
@dib-unil.bsky.social @fbm-unil.bsky.social