MATCAP1 preferentially binds an expanded tubulin conformation to generate detyrosinated and ΔC2 α-tubulin - The EMBO Journal Microtubules are cytoskeletal filaments with critical roles in cell division, cell motility, intracellular trafficking, and cilium function. In cells, subsets of microtubules are selectively marked by...

The metallopeptidase MATCAP1 preferentially binds microtubules with an expanded tubulin conformation to generate detyrosinated and ΔC2 α-tubulin
@kjverhey1.bsky.social, Puck Ohi and collaborators
link.springer.com/article/10.1...

Chromosomal instability promotes cell migration and invasion via EFEMP1 secretion into extracellular vesicles - The EMBO Journal Triple-negative breast cancer (TNBC) is characterised by high rates of chromosomal instability (CIN) and rewired intercellular communication driven by both soluble factors and extracellular vesicles (...

New paper alert! In this study, we find that cells with chromosomal instability (CIN) secrete more extracellular vesicles (EVs). These CIN-induced EVs promote migration and invasion of EV-recipient cells an EFEMP1-dependent manner both in vitro and in vivo. link.springer.com/article/10.1...

Convergent evolution of aerobic fermentation through divergent mechanisms acting on key shared glycolytic genes - The EMBO Journal As the tree of life becomes increasingly accessible to molecular investigations, describing mechanisms underlying evolutionary convergence and constraint will be crucial to understanding diversificati...

So pleased to share that this project identifying convergent evolution of aerobic fermentation in a poorly characterized genus of yeasts (Saturnispora) is now out in @embojournal.org

@hittingerlab.bsky.social @rokaslab.bsky.social @glbioenergy.bsky.social

link.springer.com/article/10.1...

Chromosomal instability promotes cell migration and invasion via EFEMP1 secretion into extracellular vesicles - The EMBO Journal Triple-negative breast cancer (TNBC) is characterised by high rates of chromosomal instability (CIN) and rewired intercellular communication driven by both soluble factors and extracellular vesicles (...

Breast cancer cells with chromosomal instability (CIN) promote cell migration and invasion of low-CIN cancer cells via secretion of extracellular vesicles transferring ECM components
@foijer-lab.bsky.social and collaborators
link.springer.com/article/10.1...

SenSet defines cell-type specific senescence signatures in the aged human lung - The EMBO Journal Cellular senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors, including DNA damage, oxidative stress, or nutrient deprivation. Although sen...

SenSet:
Melanie Königshoff @eickelbergmd.bsky.social Ziv Bar-Joseph et al develop a learning/classification algorithm to define gene signatures distinguishing senescent cells in the aged human lung
link.springer.com/article/10.1...

The H3K36me3 methyltransferase SETD2 contributes to PAF1C interactions with RNA Pol II and is required for neuronal differentiation - The EMBO Journal Chromatin modifications are essential for mammalian development, and their aberrant deposition is associated with human disease. While the mechanisms that deposit and remove histone modifications have...

The H3K36me3 methyltransferase SETD2 contributes to PAF1C interactions with RNA Pol II and is required for neuronal differentiation
Tuncay Baubec and coworkers
link.springer.com/article/10.1...

Convergent evolution of aerobic fermentation through divergent mechanisms acting on key shared glycolytic genes
@hittingerlab.bsky.social , @linder-surprise.bsky.social et al show how distinct genetic routes can converge on the same genetic outcome
link.springer.com/article/10.1...

How come giant mimivirus virions retain icosahedral symmetry like smaller viruses?
Chantal Abergel, Hugo Bisio @molbiolgv.bsky.social et al use bioinformatics, genetics & interactomics to elucidate spatial & functional organization of mimivirus virion morphogenesis
link.springer.com/article/10.1...

Fantastic teamwork by Milica Mihailovic & Aleksandra Anisimova from the Karagöz lab @gekaragoz.bsky.social @maxperutzlabs.ac.at together with the @plantophagy.bsky.social lab — Another great collaboration 🙌 within our SFB program, published in @embojournal.org
🔗 link.springer.com/article/10.1...

Global stabilization of the transcriptome in mitotic cells - The EMBO Journal In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique aspects of mitosis require substantial adaptations to gene expression. During interphase, homeostatic control of mRNA levels involves a constant balance of transcription and degradation, with a median mRNA half-life of ~2–4 h. If such short half-lives persisted in mitosis, cells would be expected to rapidly deplete their transcriptome without new transcription. Here, we report that the transcriptome is globally stabilized during prolonged mitotic delays. Median mRNA half-lives are increased >4-fold during mitotic arrest compared to interphase, buffering mRNA levels in the absence of new synthesis. Moreover, poly(A) tail-length profiles change during mitotic arrest, strongly suggesting a partial mitotic repression of deadenylation. In contrast, siRNA-directed mRNA degradation machinery remains active. We further show that mitotic mRNA stabilization depends on PABPC1&4. Depletion of PABPC1&4 during mitotic arrest reduces mRNA stability and disrupts the cells’ ability to maintain arrest, highlighting the critical physiological role of mitotic transcriptome buffering.

How can cells maintain gene expression despite minimal transcription during prolonged mitotic arrest?
@iaincheeseman.bsky.social @jimmy-ly.bsky.social et al reveal global transcriptome stabilization in mitotic cells, partly because of reduced mRNA deadenylation
link.springer.com/article/10.1...

A conserved leader–repeat hairpin prevents processing of the first CRISPR repeat, suppressing extraneous crRNA production and preserving Cas13-mediated immunity
Chase Beisel @helmholtz-hiri.bsky.social and coworkers
link.springer.com/article/10.1...

A spontaneous termination mechanism of RNA polymerase V shapes the DNA methylation landscape in plants - The EMBO Journal DNA methylation plays critical roles in eukaryotic gene silencing, genome imprinting, viral defense, and suppression of transposable elements. In plants, RNA Polymerase V (Pol V)-generated non-coding RNA guides DNA methylation through the RNA-directed DNA methylation (RdDM) pathway; however, how these RNAs are selected is unknown. Here, we show that the 3’-ends of Pol V transcripts are enriched at A-rich template DNA (A-rich-DNAT). Arabidopsis RdDM regions possess AT-rich boundaries genome-wide, suggesting that Pol V likely terminates at A-rich-DNAT, which subsequently defines the DNA methylation landscape in plants. A-rich-DNAT successfully stops Pol V transcription in vitro. Structural snapshots of Pol V transcribing A-rich-DNAT show that accumulation of unstable rU:dA pairs in the RNA-DNA hybrid promotes transcription bubble collapse and spontaneous transcription termination. These findings identify an intrinsic Pol V termination signal that shapes genomic DNA methylation patterning in plants and reveals a common mechanism for spontaneous transcription termination.

A spontaneous termination mechanism of RNA polymerase V shapes the DNA methylation landscape in plants
link.springer.com/article/10.1...

Global analysis of cancer cell responses to USP9X inhibition - The EMBO Journal 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.

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...

In ISSUE 7:
Perspective: Molecular evolution of animal aging
Review: eIF3 roles in cells and disease
Sorting nexins & hybrid endosomal coats
Purine metabolism supported by microcephaly protein WDR62
Cover: Biao Gong and colleagues
link.springer.com/journal/4431...

Mechanistic basis for selective Csm6-2 activation by cyclic penta-adenylate in a type III CRISPR-Cas system - The EMBO Journal Type III CRISPR systems generate cyclic oligoadenylate (cOA, 3 to 6 AMPs) messengers upon detecting viral RNA, activating downstream effectors to defend against viral infection. Although cOA-activated...

Selective recognition of cyclic penta-adenylated stabilizes a Csm6 tetramer and triggers allosteric activation of its HEPN ribonuclease in a Type-III CRISPR-Cas system
Zhonghui Lin, Haishan Gao and colleagues
link.springer.com/article/10.1...

Orphan nuclear receptors recruit TRIM28 to promote telomeric H3K9me3 for the ALT pathway - The EMBO Journal Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism deployed in embryonic stem cells and cancer cells. High levels of the heterochromatin mark H3 lysine 9 trimethylation (H3...

Association of orphan nuclear receptors and heterochromatin are involved in Alternative Lengthening of Telomeres – Liuh-Yow Chen and coworkers identify their link as the transcriptional corepressor TRIM28
Thanks to @reviewcommons.org for another #RefereedPreprint
link.springer.com/article/10.1...

Structural insight into ligand binding and activation of the orphan GPCR Mas1 - The EMBO Journal The Mas1 receptor, an orphan class A G-protein-coupled receptor (GPCR), plays pivotal roles in cardiovascular and anti-inflammatory regulation. Despite its therapeutic relevance, the structural mechan...

Cryo-EM structures of orphan GPCR Mas1 reveal distinctive, super-shallow hydrophobic binding pocket that accommodates diverse agonists, and a non-canonical activation mechanism distinguishing Mas1 from classical class A GPCRs
Yumu Zhang, Dehua Yang, H Eric Xu et al
link.springer.com/article/10.1...

Ca²⁺ leakage is a conserved signal for non-canonical ATG8/LC3 lipidation and membrane repair - The EMBO Journal Endomembrane damage of intracellular vesicles triggers signals that activate membrane repair in mammalian cells to restore homeostasis. However, the signals that drive diverse membrane repair recruitm...

💥Our latest @embojournal.org on membrane damage and repair. Di @dichen02.bsky.social @crick.ac.uk found that calcium is a conserved signal for ATG8/LC3 lipidation on membranes using novel probes to record calcium leakage. Congratulations Di et al!
link.springer.com/article/10.1...

FADD is recruited to activated STING oligomers to initiate caspase-mediated NF-κB activation in Drosophila melanogaster - The EMBO Journal STING is an evolutionarily conserved key regulator of innate immunity. In the model organism Drosophila melanogaster, STING activates the NF-κB-like transcription factor Relish, initially characterize...

FADD is recruited to activated STING oligomers to initiate caspase-mediated NF-κB activation in Drosophila melanogaster
Rune Hartmann, Jean-Luc Imler and coworkers
link.springer.com/article/10.1...

CDKAL1 dysfunction impairs lysine codon translation in podocytes and accelerates chronic kidney disease - The EMBO Journal Cdk5 regulatory subunit-associated protein 1-like 1 (Cdkal1) encodes a tRNA-modifying enzyme responsible for thiomethylation generating 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in the antic...

GWAS have linked tRNA-modifying enzyme CDKAL1 to diabetes but why?
Kazuhito Tomizawa and colleagues find it affects kidney function via impaired translation of lysine-rich podoycyte proteins
link.springer.com/article/10.1...

Thermostable ancestors enabled evolutionary diversification of promiscuous chemical defence enzymes - The EMBO Journal Enzymes are generally believed to evolve from promiscuous ancestors to more specialized descendants under some selection pressure related to their function. However, enzymes whose function depends on ...

Thermostable ancestors enabled evolutionary diversification of promiscuous chemical defence enzymes
Elizabeth Gillam and coworkers
link.springer.com/article/10.1...

Traffic control at the molecular scale During protein synthesis, ribosomes stall when they encounter damaged mRNA or when cells are depleted of essential factors. Unresolved, stalled ribosomes have the potential to create harmful traffic j...

see also the related Press Release:
www.maxperutzlabs.ac.at/news/latest-...

The coordinated action of UFMylation and the RQC pathways clears arrested polypeptides at the ER - The EMBO Journal Clearance of arrested nascent polypeptides resulting from ribosomal stalling is essential for proteostasis. Stalled endoplasmic reticulum (ER)-bound ribosomes are marked by ubiquitin-fold modifier 1 (...

What are the roles of UFMylation during ribosome-associated quality control?
@gekaragoz.bsky.social @plantophagy.bsky.social and colleagues find it to cooperate with RQC factors in promoting clearance of arrested nascent polypeptides at the ER
link.springer.com/article/10.1...

Microtubule end stabilisation by cooperative oligomers of Ska and Ndc80 complexes - The EMBO Journal During mitosis, properly aligned chromosomes stabilise microtubule ends with the help of kinetochores to ensure timely segregation of chromosomes. Microtubule-binding components of the human outer kin...

Proper chromosome segregation requires microtubule end capture by outer kinetochore
@vladimirvolkov.bsky.social et al show that oligomerizing interactions of Ndc80 & Ska complexes underlie their ability to stabilize microtubule ends against detachment & shortening
link.springer.com/article/10.1...

GTPase Rab11b and effector Rab11-FIP2 promote NLRP3 stability during inflammasome priming - The EMBO Journal Membrane trafficking through the trans-Golgi network has been shown to guide activation of the NLRP3 inflammasome. Rab11 GTPases and their effector Rab11-FIP2 regulate endosomal trafficking and retrog...

GTPase Rab11b and effector Rab11-FIP2 promote NLRP3 stability during inflammasome priming
Harald Husebye and colleagues
link.springer.com/article/10.1...

The coordinated action of UFMylation and the RQC pathways clears arrested polypeptides at the ER - The EMBO Journal Clearance of arrested nascent polypeptides resulting from ribosomal stalling is essential for proteostasis. Stalled endoplasmic reticulum (ER)-bound ribosomes are marked by ubiquitin-fold modifier 1 (...

Congrats Milica @alessandrick.bsky.social & everyone @gekaragoz.bsky.social lab. Glad we could contribute to this awesome story on #UFMylation & #RQC crosstalk @embojournal.org link.springer.com/article/10.1...

Ki-67 shapes the nucleolus by anchoring chromatin via its amphiphilic properties - The EMBO Journal The nucleolus, a membrane-less organelle essential for ribosome biogenesis, adopts variable shapes across cell types and in response to environmental conditions, yet the mechanisms regulating its morp...

Why do nucleoli adopt irregular shapes despite their liquid-like nature?
Sara Cuylen-Häring and colleagues find that Ki-67 mediates this irregularity by tethering chromatin at the surface and creating internal chromatin invaginations
link.springer.com/article/10.1...

FGF4 initiates X-chromosome inactivation via activating YY1 and prompting loss of pluripotency factors - The EMBO Journal X-chromosome inactivation (XCI) balances gene expression between sexes in mammals and is essential to female development. XCI initiation strictly relies on the upregulation of long noncoding RNA Xist ...

FGF4 initiates X-chromosome inactivation via activating YY1 and prompting loss of pluripotency factors
Jianhui Tian and coworkers
link.springer.com/article/10.1...

🆕 publication! The @gekaragoz.bsky.social lab shows how cells clear stalled ribosomes at the ER, preventing harmful 'traffic jams' during protein synthesis🚦Their new @embojournal.org study reveals how quality control and UFMylation team up to keep translation moving ➡️ tinyurl.com/2czj8fvp

Functional rescue of a disease-linked ERAD pathway mutation via alternative splicing - The EMBO Journal ER-associated degradation (ERAD) targets misfolded proteins in the endoplasmic reticulum (ER) for proteasomal degradation. Mutations in its most conserved branch involving the SEL1L-HRD1 complex cause...

Huilun Helen Wang, Shengyi Sun, Ling Qi et al. serendipitously discover that mouse models expressing a fatal ERAD pathway mutation in SEL1L are rescued by alternative-splicing-mediated exclusion of the defective region
link.springer.com/article/10.1...