Inlay

USP9X: understanding its cell-type-specific deubiquitination targets & mitotic arrest phenotypes in cancer cells Broad cancer cell-line screen by Philipp Schenk et al @komanderlab.bsky.social @wehi-research.bsky.social upon treatment with next-gen inhibitor WEHI-092 link.springer.com/article/10.1...

Congratulations Jake @mediocre-jake.bsky.social, Bekky Feltham and team on their phenomenal effort in putting together the E3-ome, published in Cell www.cell.com/cell/fulltex.... An extremely valuable resource for ubiquitin researchers.

WEHI researchers have found glycogen can be directly regulated using ubiquitin, in landmark findings published in Nature. The study transforms understanding into glycogen metabolism & could lead to new treatments for diseases caused by abnormal sugar storage. www.wehi.edu.au/news/sweet-d... 🧵1/2

Interested in non-proteinaceous ubiquitination, induced proximity or glycogen? Then you should have a look at our newest article, “Ubiquitination of glycogen and metabolites in cells and tissues”, just published in Nature: www.nature.com/articles/s41...

Passionate about ubiquitin biology, its mechanistic underpinnings and therapeutic exploitation? We are looking for a PhD student or postdoc to join our team. Applications and informal inquiries welcome! www.mpinat.mpg.de/19-26?c=3895...

We posted a biorxiv preprint on structural bioinformatics, AlphaFold modeling & machine learning on predicting specificity of E3 ligase ring domains for different E2 enzymes. 1/4 Preprint: www.biorxiv.org/content/10.6... Models/data (UbiqCore website): dunbrack.fccc.edu/ubiqcore

The ubiquitin-specific protease (USP) USP9X is a human deubiquitinase (DUB) with a large number of described targets and cellular roles. In cancer, USP9X is found as an oncogene or as a tumour suppressor depending on context, and its utility as a target for cancer therapy remains unclear. We here describe WEHI-092, a piperazine-based USP9X-specific small-molecule inhibitor, which binds to a unique region in the USP9X Fingers-subdomain, distinct from known DUB-inhibitor binding sites. Using proteomics and ubiquitinomics, we show that USP9X targets distinct substrates compared to USP7, yet the substrate profile of USP9X varies significantly across cancer cell lines. We reveal a core set of 17 proteins commonly regulated by USP9X in most cell lines, which we consider as proximal biomarkers for USP9X inhibition. Consistent with proteomics, we show in unrelated cell lines that WEHI-092 treatment arrests the cell cycle in metaphase without inducing cell death. This explains growth suppression in long-term clonogenic assays in most cancer cell lines, and positions USP9X inhibitors as a new class of selective mitotic poisons.

Check out our latest paper on the ubiquitination of glycogen in cells and tissues! Congratulations to Marco Jochem (@marcojochem.bsky.social) and Simon Cobbold for leading this study and to collaborators @craigagoodman1.bsky.social, @pgregorevic.bsky.social, Kai Hofmann and Thomas Hermanns.

We show that the E3 ubiquitin ligase DTX2 creates a dual hybrid ADP-ribosyl-ubiquitin mark (ADPr-Ub) at DNA damage sites, driving the recruitment of RNF114, RNF138, and RNF166 proteins independently of HPF1. journals.plos.org/plosbiology/...

Recent studies have shown that ADP-ribose modifications can be further modified by ubiquitin (ADPr-Ub), but there are still major gaps in our knowledge around this modification and its role in the DNA damage response. This study biochemically characterises the amino acid specificity for ADPr-Ub production and its recognition by E3 ubiquitin ligases.

WEHI researchers have led a major global effort to create the first authoritative atlas for E3 ligases, resolving more than 18 years of inconsistencies in the ubiquitin field. Study led by Dr Ngee Kiat ‘Jake’ Chua & Dr Rebecca Feltham in @cellpress.bsky.social www.wehi.edu.au/news/new-enz...