Most of the experiments were done during Evelina’s Masters project in the lab, and she was brilliantly supervised and supported by Brianda Hernandez Moran and Gillian Taylor.

This reveals a synthesis dependent ceiling on degradation, with implications for:
• interpreting preclinical degrader data
• resistance mechanisms
• genotype guided therapy design

Using a controlled cellular system (dTAG + TetOn3G), we found:
✅ Stabilising mutations don’t limit PROTAC action—degradation resets protein levels to the same baseline.
❌ Increased transcription raises target protein levels both pre and post treatment.

Our recently published saturation genome editing study characterised mutations which stabilise ß-catenin in cancer: www.nature.com/articles/s41...

Less frequently, ß-catenin gets upregulated transcriptionally.

Both mechanisms raise protein levels—but do degraders “see” them the same way?

🔬 New preprint:
How does the mode of oncogene activation shape PROTAC efficacy?

Led by Evelina Gudauskaite, we ask whether stabilising mutations vs transcriptional upregulation have distinct consequences for targeted protein degradation.

www.biorxiv.org/content/10.6....

Dr Tom Deegan from University of Edinburgh awarded The Colworth Medal by The Biochemical Society 2027 Awards.

Congratulations to Tom Deegan who receives the Colworth Medal in 2027! Pioneering work from the Deegan Lab has redefined our understanding of eukaryotic DNA replication and provided conceptual and technical frameworks that continue to drive new discoveries across molecular biology.

Assessing the suitability of deubiquitylases as substrates for targeted protein degradation Tong et al. describe a chemical genetic system to evaluate the degradability of deubiquitylase (DUBs) enzymes by PROTACs that do not inhibit their catalytic activity. They find that some Dubs are readily degradable, others resist degradation through auto-deubiquitylation, and some are inherently poor proteasome substrates because they are difficult to unfold.

Online now! Online now! Assessing the suitability of deubiquitylases as substrates for targeted protein degradation #chembiol

Thanks Miguel!

Thanks Pradeep

This was a team effort involving effort from many including IGC colleagues @jmarshlab.bsky.social @csemple.bsky.social @ailithewing.bsky.social, @bioggrimes.bsky.social, plus others not on bluesky. Important contributions from Agavni Mesropian and others in the group of Josep M Llovet in Bacelona

An elegant approach using a mix of technologies and making the most of resources generated over many years of research into the canonical Wnt pathway.
And results which have the potential to andvance personalised treatment for some forms of cancer. Congrats @andrewwood.bsky.social and collaborators!

New map reveals cancer mutation effects | Institute of Genetics and Cancer | Institute of Genetics and Cancer Scientists have created a complete map showing how hundreds of possible mutations in a key cancer gene influence tumour growth.

Read more about a new map showing how hundreds of possible mutations in a key cancer gene influence tumour growth 👉 edin.ac/3NTaToX
@andrewwood.bsky.social
@roslininstitute.bsky.social
@unileiden.bsky.social
@koc-university.bsky.social
@cmvm-edinburghuni.bsky.social

...and perhaps most excitingly:
- HCC tumours with high effect CTNNB1 mutations tend to be immune excluded, whereas those with low effect mutations do not.

- Cancers originating in different human tissues favour CTNNB1 mutations occupying distinct ranges of activation.
- Hepatocellular carcinoma (HCC) patients with CTNNB1 mutations can be stratified into groups with low or high Wnt pathway activation

To cut a long story short:
- Structure/Function analysis helps to understand why some CTNNB1 mutations disrupt degron function while others do not.
- Common driver mutations show diverse levels of Wnt pathway activation.

This is the product of a long-running collaboration between my lab @uoe-igc.bsky.social, and Peter Hohenstein’s group @roslininstitute.bsky.social @unileiden.bsky.social, with wet-lab work led by Anagha Krishna and Derya Ozdemir, dry-lab work led by Alison Meynert and Martijn Kelder.

Today in @natgenet.nature.com, we report a saturation genome editing study that systematically dissects the degron of β-Catenin, which contains 5 of the 25 most frequently mutated regions of the human cancer genome, and >70 recurrent missense mutations.

rdcu.be/e1Tvk

Our Best Models Working Group can offer advice on the use of a range of model systems.

The next in our series highlighting our diverse expertise features Dr Andrew Wood, whose lab uses genome editing and targeted protein degradation to study genetic disease using cell lines, organoids, and mice.

How kind of you!

Today's a good day to remember Rosalind Franklin, British chemist and X-ray crystallographer whose untimely death meant three men shared a Nobel prize for discovering the structure of DNA for which she'd done most of the work.

With storm Amy approaching, it’s an ideal time to get your SLiPERs on!

On 14th November, we are once again holding our Network Science Day in York, which is an exciting opportunity for Network members and non-members to engage and develop new collaborations!

The meeting is free to attend. Find out more and register by emailing us at Genetics_Network@har.mrc.ac.uk.

One mother for two species via obligate cross-species cloning in ants - Nature In a case of obligate cross-species cloning, female ants of Messor ibericus need to clone males of Messor structor to obtain sperm for producing the worker caste, resulting in males from the same moth...

Look at this crazy thing!
www.nature.com/articles/s41...

Understanding the Protein Tagging Problem: A New Study from the NMGN Degron Tagging Cluster | National Mouse Genetics Network Celebrating Research Specialists: Driving Innovation in Mouse Genetics Research specialists are often the unsung heroes in biomedical research groups, providing continuity in long-term research progra...

Nice write up on the @mrcmousenetwork.bsky.social
website, highlighting the awesome work of first author Gillian Taylor, is available here: nmgn.mrc.ukri.org/news/underst...

Our manuscript characterising tissue-specific consequences of tagged protein fusions in CRISPR-engineered mice is now online @PLOSGenetics. journals.plos.org/plosgenetics.... Thanks again to all coauthors, reviewers and editors for a smooth publication process. Brief summary below.

Why We Still Need Animal Research in a World of AI and Organoids The portrayal of uncaring scientists without any thought for the animals being used in their research is far from the truth.

www.genengnews.com/topics/trans...

We really appreciated your contribution to this work, and for developing DEGRONOPEDIA which we use often 🙏

Oliver Smithies was born 100 years ago today. Best known for gene targeting in mice, for which he shared the 2007 Nobel, he also developed starch gel electrophoresis in the 1950s. I met him once and remember him being very gracious and thoughtful.
#genetics #OTD

www.nobelprize.org/prizes/medic...

Banger! Thanks @cellysally.bsky.social

@cilialab.bsky.social @wpokrzywa.bsky.social @lumirare.com @cribdealmeida.bsky.social