bims-ginsta Biomed News
on Genome instability
Issue of 2026–10–04
thirty-two papers selected by
Jinrong Hu, National University of Singapore
  1. Emergence of the Endoderm in the Mammalian Embryo: From Cell Fate Specification to Gut Tube Formation.
  2. Spatiotemporally primed coelomic epithelium and supporting-like cells establish the dual origin of granulosa cells.
  3. Regulation of mRNA poly(A) tail length governs mammalian body plan formation in gastruloids.
  4. The endo-lysosomal system drives lumen formation in a human epiblast model.
  5. Quantification of lipid sorting during clathrin-mediated endocytosis.
  6. Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
  7. Mitochondria-ER-lipid droplet crosstalk regulates metabolic adaptation to shear stress via VMP1.
  8. Transcription termination factor 2 (TTF2) prevents premature rRNA synthesis during mitotic exit.
  9. Parental B-MYB/FOXM1 controls mitotic E2F to determine daughter cell fate.
  10. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
  11. A two-hit mechanism triggers autoimmune hair loss.
  12. Cotranslational membrane protein biogenesis by an EMC-bound translocon.
  13. A genetically encoded redox bottleneck constrains human developmental rate.
  14. Ubiquitin chain editing promotes p97/VCP-dependent removal of RPA from DNA.
  15. ATM safeguards DNA replication by restraining pathological repriming at endogenous base lesions.
  16. Allele-specific expression is associated with lower translational efficiency in mouse embryos and stem cells.
  17. A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition.
  18. Mitotic shape changes drive spatiotemporally segregated cell-contact rearrangements in a proliferating epithelium.
  19. Multiomic proximity labeling in vivo by D-amino-acid-activated peroxidase reaction.
  20. Starvation improves epithelial fitness by selectively extruding DNA damaged cells.
  21. SRSF1 modulates the dark nucleolar cap pH to restore nucleolar integrity and function.
  22. Mechanical stress remodelling drives epithelial-mesenchymal transition in the tumour microenvironment.
  23. Zyxin and LPP differ in their sensing of strained actin filaments at tricellular junctions.
  24. Single-molecule chromatin tracing reveals a diversity of megabase heterochromatin domains.
  25. Squamous epithelial morphogenesis and mechanobiology across the lifetime of dynamic barrier tissues.
  26. Modeling Heart Failure With Preserved Ejection Fraction Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
  27. Loss of the tumor suppressor p53 generates a signaling gradient that drives epithelial clonal expansion.
  28. Written in development and lost in ageing: the grammar of cellular identity.
  29. A phosphoproteome atlas of human cell lines reveals the landscape of kinase activity.
  30. The early RNA decay factor ZC3H18 directs first intron splicing.
  31. Bidirectional redistribution of actomyosin drives epithelial invagination in ascidian siphon tube morphogenesis.
  32. HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death.
  1. Annu Rev Cell Dev Biol. 2026 Oct;42(1): 361-382
    Emergence of the Endoderm in the Mammalian Embryo: From Cell Fate Specification to Gut Tube Formation.
    Sonja Nowotschin, Anna-Katerina Hadjantonakis.
      The endoderm is the embryonic tissue that gives rise to vital organ systems in both the developing embryo and adult animal. Cells with a definitive (embryonic) endoderm identity emerge from the pluripotent epiblast at gastrulation, and go on to form the gut tube, which develops into the epithelial component of the digestive and respiratory tracts. In this review, we discuss the mechanisms driving endoderm emergence and morphogenesis, including key epithelial-mesenchymal and mesenchymal-epithelial transitions, the mechanical forces driving gut tube formation, and the patterning events that subdivide the gut tube into different organ territories. We also elaborate on the role of the primitive endoderm, which emerges earlier at the blastocyst stage and contributes mainly to extraembryonic tissues in amniotes-such as the yolk sacs-essential for the embryo's nutrition and protection. Together, this review provides an overview of the current understanding of early endoderm development and highlights key open questions.
    Keywords:  blastocyst; cell fate specification; endoderm; gastrulation; gut tube; ventral folding
    DOI:  https://doi.org/10.1146/annurev-cellbio-111524-021734
  2. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2615939123
    Spatiotemporally primed coelomic epithelium and supporting-like cells establish the dual origin of granulosa cells.
    Cyril Djari, Chloé Mayère, Maëva Guy, Aitana Perea-Gomez, Laura Bellutti, Paul Barreau, Herta Ademi, Agathe Rozier, Anthony S Martinez, Tyler J Gibson, Françoise Kühne, Cassandre Guérin, Dagmar Wilhelm, Gabriel Livera, Jennifer McKey, Marie-Christine Chaboissier, Serge Nef.
      Ovarian organogenesis relies on the coordinated specification of supporting and steroidogenic lineages from multipotent progenitors of the coelomic epithelium. However, how these progenitors adopt distinct fates and differentiate into pregranulosa cells and steroidogenic progenitors of theca cells remain poorly understood. Here, we show that the dynamics of ovarian somatic lineage specification are conserved between human and mouse. Coelomic epithelial cells covering the fetal ovaries are heterogeneous and already biased toward supporting or steroidogenic fates. This priming is spatially and temporally organized, influenced by proximity to the mesonephros, and characterized by a transient coexistence of both progenitor types before resolving into predominantly supporting-biased cells. In mice, local delamination of these primed epithelial progenitors seeds intragonadal domains that give rise to pregranulosa and steroidogenic progenitors. We further demonstrate that these fetal steroidogenic progenitors generate adult stromal and theca cells. In addition, we uncover that granulosa cells arise from two distinct sources: Coelomic epithelium-derived progenitors generate the majority of cortical granulosa cells forming the long-lived follicle reserve, whereas supporting-like cells contribute to a smaller granulosa subpopulation. Together, these findings establish a revised model of ovarian development in which early spatial patterning of coelomic epithelial progenitors directs lineage specification, reveals the dual origin of granulosa cells, and defines the developmental origin of theca cells.
    Keywords:  coelomic epithelium; fate restriction; granulosa cells; lineage tracing; ovarian development
    DOI:  https://doi.org/10.1073/pnas.2615939123
  3. Nat Commun. 2026 08 29. pii: 10390. [Epub ahead of print]17(1):
    Regulation of mRNA poly(A) tail length governs mammalian body plan formation in gastruloids.
    David Taborsky, Fabiola Valdivia-Francia, Pablo Serrano, Sukalp Muzumdar, Neguin Ranjbar, Laura Llop-Grau, Guillermo Tellez, Pjeter Gjonlleshaj, Clara Duré, Peter F Renz, Ramona Weber, Merve Yigit, Umesh Ghoshdastider, Aleksei Mironov, Katie Hyams, Stefano Vianello, Mihaela Zavolan, Ori Bar-Nur, Matthias P Lutolf, Ataman Sendoel.
      The establishment of the body plan during gastrulation represents a hallmark of animal life. It emerges from the interplay of gene-regulatory programs and positional cues, yet how these signals are integrated post-transcriptionally remains largely unexplored. Here, we combine the scalability of mouse gastruloids with a single-cell CRISPR screening platform to functionally dissect germ layer specification at single-cell transcriptomic resolution. Focusing on post-transcriptional regulation, we systematically map drivers of mesodermal and endodermal fate and identify the deadenylase Cnot8. Loss of Cnot8 leads to widespread poly(A) tail elongation and transcript stabilization, shifting mesoderm differentiation toward ectopic notochord fate, thereby profoundly impacting axial patterning. Collectively, our findings identify mRNA deadenylation as a fundamental mechanism linking cellular identity with morphogenetic signaling during mammalian body plan formation.
    DOI:  https://doi.org/10.1038/s41467-026-76897-3
  4. Nat Commun. 2026 Aug 27. pii: 10255. [Epub ahead of print]17(1):
    The endo-lysosomal system drives lumen formation in a human epiblast model.
    Anusha Rengarajan, Sicong Wang, Chien-Wei Lin, Lauren E Elberfeld, Jenna C Wettstein, Amber E Carleton, Nikola Sekulovski, Linnea E Taniguchi, Bailey E Schultz, Mara C Duncan, Kenichiro Taniguchi.
      Epiblast lumen formation is a critical step that occurs during human embryo implantation. It begins with the apicosome, an apical compartment partly derived from endocytosed material. However, how the endo-lysosomal system contributes to apicosome formation and later lumen development remains unclear. Using a human pluripotent stem cell-derived model of epiblast formation, we show that apicosome formation is accompanied by transient expansion of early endosomes, late endosomes, and lysosomes, as well as the formation of hybrid compartments with features of both early and late endo-lysosomal stages. These changes depend on the RAB GTPases RAB35 and RAB7, which are required for proper apicosome formation and lumen morphology of the human epiblast model. Our findings identify RAB35- and RAB7-dependent endo-lysosomal remodeling as a key mechanism driving apical membrane morphogenesis during human epiblast development.
    DOI:  https://doi.org/10.1038/s41467-026-77140-9
  5. Nat Cell Biol. 2026 Sep 29.
    Quantification of lipid sorting during clathrin-mediated endocytosis.
    H Mathilda Lennartz, Susana da Costa Nunes, Kristin Böhlig, Aditya Chhatre, Radek Šachl, Sascha M Kuhn, Lior Moneta, Pavel Barahtjan, Wan Yee Yau, Juan M Iglesias-Artola, Martin Hof, Lukáš Opálka, Carl D Modes, Alf Honigmann, André Nadler.
      Clathrin-mediated endocytosis is a major transport route for proteins from the plasma membrane to the interior of the cell. While the recruitment of cargo proteins to clathrin-coated pits is well understood, it remains an open question whether lipids are also sorted by this process. Here, to address this question, we combined super-resolution stimulated emission depletion imaging of bifunctional lipid probes with mathematical modelling. Quantification of ten different lipid species revealed significant differences in pit partitioning, ranging from slight enrichment to moderate exclusion. We find that the lipid asymmetry in the plasma membrane is sufficient to explain the observed trend. Taken together, our findings imply that clathrin-mediated endocytosis has a minor selectivity for cytoplasmic leaflet lipids, but overall does not substantially contribute to lipid sorting compared with non-vesicular trafficking.
    DOI:  https://doi.org/10.1038/s41556-026-02068-7
  6. Nat Aging. 2026 Sep 29.
    Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ.
    Fabian Finger, Mikkel Frost, Shinya Watanabe, Tao Ma, Taewook Kang, Dipsikha Biswas, Ruben Zapata-Perez, Vincent Anton, Lucile Dollet, Lasse K Markussen, Nanami Senoo, Iuliia Karavaeva, Astrid Linde Basse, Oksana Dmytriyeva, Tara TeSlaa, Jesper F Havelund, Amy M Ehrlich, Marta Moreno-Torres, Caio Yogi Yonamine, Nicoline R Andersen, Ida Blom, Francisco Garcia-Carrizo, Piyarat Siripoksup, Magnus Asping, Thomas S Nielsen, Marcus Nygård, Anders B Klein, Andrey Tvardovskiy, Trine S Nicolaisen, Carlos Durantez-Fernández, Klaus Qvortrup, Clara Prats, Joshua D Rabinowitz, Christoffer Clemmensen, Lykke Sylow, Juleen R Zierath, Jonas T Treebak, Tim J Schulz, Trisha J Grevengoed, Steven M Claypool, Julien Prudent, Rob C I Wüst, Susanne Mandrup, Riekelt H Houtkooper, Kei Sakamoto, Nils J Færgeman, Martin R Larsen, Katsuhiko Funai, Steen Larsen, Zachary Gerhart-Hines.
      Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.
    DOI:  https://doi.org/10.1038/s43587-026-01227-7
  7. Curr Biol. 2026 Oct 02. pii: S0960-9822(26)01198-X. [Epub ahead of print]
    Mitochondria-ER-lipid droplet crosstalk regulates metabolic adaptation to shear stress via VMP1.
    Maria Laura Rojas, Maribel Lara Corona, Carla Alemany, Juliane Da Graça, Nicolas Goudin, Ivan Nemazanyy, Ida Chiara Guerrera, Aurore Claude-Taupin, Etienne Morel.
      Kidney tubular epithelial cells adapt to physiological urinary flow through rapid metabolic remodeling,1,2 but the mechanisms coordinating this response remain poorly understood. Shear stress promotes lipid catabolism and mitochondrial activity in these cells,3,4 but how changes in mitochondrial dynamics contribute to this metabolic adaptation remains poorly understood.5,6,7,8,9 Here, we show that physiological shear stress rapidly remodels mitochondrial morphology in kidney epithelial cells in vitro and in the zebrafish pronephros, characterized by the emergence of a distinct pool of donut-shaped mitochondria. This remodeling is accompanied by a transient stabilization of mitochondria-endoplasmic reticulum (ER) contact sites (MERCs), occurring independently of any increase in overall ER volume. Using split-TurboID proximity labeling and mass spectrometry, we detected subtle changes in the molecular environment of MERCs during shear stress, including increased proximity of proteins implicated in lipid transfer and membrane contact-site biology. We further show that shear stress promotes the formation of ER-lipid droplet (LD)-mitochondria contact sites and facilitates the local transfer of fatty acids from LDs to mitochondria. This lipid transfer requires vacuolar membrane protein 1 (VMP1), a component of membrane contact sites, whose depletion perturbs LDs and compromises metabolic adaptation to shear stress. Together, our findings identify ER-LD-mitochondria contact sites as dynamic platforms that coordinate lipid transfer and mitochondrial remodeling during the early adaptation of kidney epithelial cells to physiological shear stress, highlighting membrane contact sites as important components of the cellular response to mechanical forces.
    Keywords:  contact sites; endoplasmic reticulum; kidney epithelial cells; lipid droplets; metabolic adaptation; mitochondria; shear stress; zebrafish
    DOI:  https://doi.org/10.1016/j.cub.2026.09.021
  8. Life Sci Alliance. 2026 Dec;pii: e202603841. [Epub ahead of print]9(12):
    Transcription termination factor 2 (TTF2) prevents premature rRNA synthesis during mitotic exit.
    Catarina Pedro, Laura Tovini, Catarina Peneda, Mia Maesano Krapinec, Raquel A Oliveira.
      Mitosis poses major challenges to transcription, as gene expression is silenced and must be restored upon mitotic exit. These processes are regulated by Cdk1-dependent phosphorylation. Additional mechanisms, including transcription termination factor 2 (TTF2)-mediated removal of nascent transcripts, reinforce transcriptional shutdown. How these regulatory layers control different RNA polymerases and influence reactivation at mitotic exit remains poorly understood. Here, we probed how TTF2 controls transcription of distinct RNA classes, using polymerase-specific perturbations and nascent RNA labelling across mitosis. Loss of TTF2 led to accumulation of chromatin-associated transcripts during metaphase, predominantly RNA polymerase II-derived, consistent with its role in transcriptional clearance. Unexpectedly, TTF2 depletion caused premature RNA polymerase I reactivation during anaphase, resulting in unscheduled rRNA synthesis and early nucleolar protein recruitment. These findings place TTF2 as a novel regulator of RNA polymerase I reactivation at mitotic exit. Disruption of this control persists beyond mitosis, resulting in nucleolar fragmentation in interphase. These findings reveal TTF2 as an important regulator that interfaces with multiple RNA polymerases through distinct modes, coordinating transcriptional shutdown and timely reactivation across mitosis.
    DOI:  https://doi.org/10.26508/lsa.202603841
  9. bioRxiv. 2026 Sep 22. pii: 2026.09.21.753170. [Epub ahead of print]
    Parental B-MYB/FOXM1 controls mitotic E2F to determine daughter cell fate.
    David L Rosenthal, Tatsuki Tsuruoka, Yumi Konagaya, Bo Gong, Vinodhini Govindaraj, Samsara W Upadhya, Nalin Ratnayeke, Debarya Saha, Wenxin Xia, Mary N Teruel, Tobias Meyer.
      Mitogens trigger cell-cycle entry by activating E2F at the restriction point, which is followed by B-MYB/FOXM1 activation and progression to mitosis. How mitogens control continued cycling and cell-cycle exit after the restriction point is not well-understood. By developing an E2F and B-MYB/FOXM1 dual transcriptional biosensor system, we show that S/G2 phase duration is set by timed mitogen-regulated B-MYB/FOXM1 activation, while E2F activity gradually declines before mitosis. As a striking consequence, rapid B-MYB/FOXM1 activation shortens S/G2, delivering high mitotic E2F activity to daughter cells which keeps them cycling. Delayed B-MYB/FOXM1 activation prolongs S/G2, depleting mitotic E2F which drives daughters to quiescence. When S/G2 is further prolonged, partially activated B-MYB/FOXM1 frequently reverts, triggering mitotic bypass and polyploid quiescence. Thus, B-MYB/FOXM1 governs a tri-directional "G2 restriction point" where cells commit to continued cycling through early B-MYB/FOXM1 activation; cell-cycle exit through delayed B-MYB/FOXM1 activation; or mitotic bypass by B-MYB/FOXM1 inactivation.
    DOI:  https://doi.org/10.64898/2026.09.21.753170
  10. Science. 2026 Oct;394(6819): eadz4797
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G Sustarsic, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucińska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew P Gillum, Terry D Hinds, Raymond E Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W Snyder, Daniel J Fazakerley, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator-activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl-coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.
    DOI:  https://doi.org/10.1126/science.adz4797
  11. Nature. 2026 Sep 30.
    A two-hit mechanism triggers autoimmune hair loss.
    Jun Cui, Peng Wu, Ying Chang, Yi Yu, Zhi Gao, Yejing Ge, Bin Li, Huanwei Huang, Jianmin Chang, Ting Chen.
      Autoimmune diseases arise from a breakdown of immune tolerance, yet the mechanisms that initiate tissue-specific autoimmunity remain poorly understood1-4. Here we identify a two-hit mechanism in which immune dysregulation and physiological neural activation converge to trigger autoimmune alopecia. We show that transient depletion of regulatory T (Treg) cells during the anagen phase of the hair cycle, but not during telogen, induces CD8+ T-cell-mediated destruction of immune-privileged hair follicle stem cells (HFSCs), resulting in hair loss. This anagen-restricted susceptibility depends on sympathetic nerve activity, which is physiologically elevated during anagen: sympathetic denervation prevents disease, whereas psychological stress or optogenetic activation of sympathetic nerves renders otherwise resistant telogen skin susceptible to autoimmune attack after Treg cell depletion. Mechanistically, sympathetic noradrenaline signalling through HFSC-intrinsic ADRB2 promotes physiological reactivation of endogenous retroviruses (ERVs) in anagen HFSCs. Under conditions of Treg cell depletion, this ERV-associated state drives autoimmune pathology by engaging AIM2-dependent innate immune activation and pathogenic CD8+ T cell responses. Accordingly, genetic ablation of Aim2 or pharmacological inhibition of ERV reverse transcription protects against disease development. Together, these findings show that physiological sympathetic activity establishes a transiently vulnerable epithelial state, whereas Treg cells prevent this state from progressing to tissue-specific autoimmunity. This neuro-epithelial-immune circuit links hair-cycle state to the breach of HFSC immune privilege and the initiation of autoimmune alopecia.
    DOI:  https://doi.org/10.1038/s41586-026-11098-y
  12. Nat Struct Mol Biol. 2026 Sep 28.
    Cotranslational membrane protein biogenesis by an EMC-bound translocon.
    Madeline G Rollins, Josephine Tang, Yu Wan, Arunkumar Sundaram, Haoxi Wu, Qianru Li, Juliette Fedry, Ramanujan S Hegde, Zhe Ji, Robert J Keenan.
      Secretory and membrane protein biogenesis occurs at ribosome-bound translocons in the endoplasmic reticulum (ER) membrane. Translocons consist of the Sec61 protein-conducting channel and various maturation factors including chaperones, modification enzymes and membrane insertases, which assemble dynamically in response to the biogenesis needs of a nascent polypeptide. In human cells, nascent multipass membrane proteins utilize the ER membrane protein complex (EMC) and the multipass translocon (MPT), but how these factors are deployed during biogenesis is unknown. Here we combine selective ribosome profiling, cryo-electron tomography and site-specific photocrosslinking to reveal the substrate range, timing and mechanism of EMC recruitment. We show that multipass proteins initially engage the MPT for insertion and chaperoning, with EMC being recruited when substrates begin to exceed the cytosolic or intramembrane capacity of MPT. Substrate-engaged EMC is observed at the interface between the MPT's protected membrane cavity and the bulk ER membrane, where it is poised for insertion, chaperoning and assembly. These results show how EMC and MPT cooperate at the ribosome-bound translocon to facilitate multipass membrane protein biogenesis.
    DOI:  https://doi.org/10.1038/s41594-026-01889-2
  13. bioRxiv. 2026 Sep 13. pii: 2026.09.10.750701. [Epub ahead of print]
    A genetically encoded redox bottleneck constrains human developmental rate.
    Gabriel E Valdebenito, Jack P Madden, Carolina Mendez, Leslie M Azurdia, Xintao Zhu, Siyu Chen, Diana Atlas, Katherine Introcaso, Hao Zhang, Yahui Wang, Fangcong Dong, Rohit Sharma, Vamsi K Mootha, Gary J Patti, Margarete Diaz-Cuadros.
      The intrinsically slow pace of human development poses challenges for regenerative medicine and disease modeling. This trait is attributed to low metabolic rates, yet the endogenous mechanisms determining species-specific metabolic flux remain unknown. Here, we identify coupling between glycolytic NADH production and mitochondrial oxidation through the glycerol-3-phosphate (G3P) shuttle as a genetic bottleneck constraining human developmental tempo. Using stem cell-derived models of the segmentation clock, an oscillator whose period reflects developmental rate, we show that low expression of the G3P shuttle enzyme GPD1L limits NADH oxidation in human progenitors compared to mouse. Overexpressing GPD1L boosts metabolic flux, accelerating the segmentation clock, cell cycle, and differentiation across germ layers. G3P-mediated redox coupling is thus a genetically encoded, rate-limiting mechanism that sets the tempo of human development.
    DOI:  https://doi.org/10.64898/2026.09.10.750701
  14. Mol Cell. 2026 Oct 01. pii: S1097-2765(26)00621-0. [Epub ahead of print]86(19): 3897-3914.e18
    Ubiquitin chain editing promotes p97/VCP-dependent removal of RPA from DNA.
    Matthew Drake, Xianzhen Zhou, Alexandra McStea, Benjamin Foster, Kay Yi Chong, Martin Attwood, Leslye Roca Burgos, Laura Bennett, Sneha Anand, Merve Kaplan, Jessica J Lu, Vaishnavi Ravikumar, Marjorie Fournier, Elena Navarro-Guerrero, Michael Ranes, Weston B Struwe, Christopher Staples, Daniel Ebner, Ian Gibbs-Seymour.
      DNA repair requires dynamic control of proteins on single-stranded DNA (ssDNA), yet how ubiquitin signaling regulates ssDNA-bound factors remains poorly understood. Here, we identify in human cells a ubiquitin chain-editing mechanism that promotes extraction of replication protein A (RPA) from ssDNA. We show that RPA stimulates the deubiquitinase ZUP1 and enhances its activity toward K63 linkages within ubiquitin chains. In response to DNA damage, RPA is modified with branched K48-K63 ubiquitin chains. ZUP1 selectively removes K63 linkages from these chains, remodeling the ubiquitin signal on RPA. We show that ZUP1-mediated editing of branched ubiquitin chains promotes p97/VCP-dependent removal of ubiquitinated RPA from ssDNA. Loss of ZUP1 causes accumulation of branched ubiquitin chains on RPA and pathological RPA trapping on ssDNA, resulting in elevated ssDNA signaling and genome instability. Together, our findings identify ubiquitin chain editing as a mechanism that controls RPA dynamics on ssDNA and enables p97/VCP-mediated protein extraction during DNA repair.
    Keywords:  DNA repair; DUBs; RFWD3; RPA; VCP; ZUP1; deubiquitinases; genome stability; p97; ssDNA; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.004
  15. Mol Cell. 2026 Sep 28. pii: S1097-2765(26)00626-X. [Epub ahead of print]
    ATM safeguards DNA replication by restraining pathological repriming at endogenous base lesions.
    Lucia Sommerova, Ashleigh King, J Ross Chapman.
      Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit homologous recombination (HR) deficiency in BRCA1/2-mutant cancers to induce synthetic lethality. PARPi also kill ataxia telangiectasia-mutated (ATM)-deficient cells, but the underlying mechanism has remained unclear. Here, we define the mechanism of PARPi cytotoxicity in mammalian ATM-deficient cells, uncovering a critical role for ATM in DNA replication. In the absence of ATM, unrestrained PRIMPOL-dependent repriming at oxidative base lesions generates post-replicative DNA gaps that activate PARP. This defect is driven by aberrant BRCA1-A recruitment to stalled replication forks in ATM-deficient cells, suppressing HLTF/ZRANB3-mediated replication fork slowing. These DNA gaps require HR for repair and underlie PARPi synthetic lethality. Suppressing repriming or base excision repair, or reducing oxidative stress, alleviates these defects. Our findings reveal how spontaneous oxidative DNA damage synergizes with dysregulated replication to drive PARPi sensitivity, establishing a paradigm of post-replicative repair addiction in ATM-deficient cells and linking oxidative DNA damage to genome instability in ataxia telangiectasia.
    Keywords:  ATM; BER; DNA replication; PARP inhibitors; ataxia telangiectasia; endogenous DNA damage; homologous recombination; replication fork dynamics; replication stress
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.006
  16. bioRxiv. 2026 Sep 10. pii: 2026.09.08.750229. [Epub ahead of print]
    Allele-specific expression is associated with lower translational efficiency in mouse embryos and stem cells.
    Dayea Park, Angélica Liechti, David Gatfield, Can Cenik.
      An mRNA's cytoplasmic fate can be shaped by its transcriptional history, its modifications and associated protein complexes. Allele-specific expression (ASE), in which a gene's two alleles are transcribed unequally, provides a natural experiment given that the alleles can differ in sequence or chromatin state, yet their transcripts share the same cytoplasm. We previously found lower translational efficiency (TE) among genes with ASE in early mouse embryos. Because that observation came from one cross direction and from preimplantation stages only, sequence-dependent and parent-of-origin-dependent ASE could not be separated, and whether the association held in other cell types remained unknown. Here we addressed both by generating RNA sequencing and ribosome profiling data from reciprocal-cross mouse 8-cell embryos, individual embryonic stem cell clones, neural progenitor cells, and adult tissues. In 8-cell embryos, both sequence-dependent and parent-of-origin-dependent ASE were associated with lower TE. Genes with ASE at the 8-cell stage also had lower protein abundance at the subsequent morula stage. Ribo-ITP, which enables ribosome profiling from single clones, allowed assessing the relationship between ASE and TE in individual embryonic stem cell clones. We found that TE was lower wherever a gene was allelically imbalanced, and the reduction was larger where that imbalance was consistent across clones. The same association held in neural progenitors, and when ASE was defined from independent published datasets, but was not detected in adult tissues. Allelic imbalance in transcription is therefore accompanied by reduced translation of the resulting mRNAs, though the intermediate carrying allelic information to the translation machinery remains unidentified.
    DOI:  https://doi.org/10.64898/2026.09.08.750229
  17. Nat Cardiovasc Res. 2026 Sep 28.
    A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition.
    Yi Fan, Dakota J Nuttall, Yi Zhao, Dina Abbasian, Clarissa Shoffler, Christopher Petucci, Wyatt G Paltzer, Yu-Ling Chang, James Marchant, Diana Presas-Ramos, Kai P Atlass, Stephen A Nemr, Jiyoung Bae, Sanjeev S Ranade, Alexandre R Colas, Xiao Li, James F Martin, Ahmed I Mahmoud.
      Cardiac regeneration is limited in the adult mammalian heart because of restricted cardiomyocyte proliferation and persistent fibrosis. We previously demonstrated that transient pharmacological inhibition of succinate dehydrogenase (SDH) with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific Sdhb deletion dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function. SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked and H3K27me3-marked chromatin states in cardiomyocytes and fibroblasts. Integration of CUT&RUN, chromatin accessibility and transcriptional profiling identified regulatory targets linking metabolic and epigenetic remodeling to regenerative responses. Together, these findings establish SDH as a multicellular regulator of cardiac regeneration and define distinct cell-specific mechanisms contributing to the regenerative effects of transient pharmacological SDH inhibition.
    DOI:  https://doi.org/10.1038/s44161-026-00881-9
  18. Curr Biol. 2026 Sep 30. pii: S0960-9822(26)01188-7. [Epub ahead of print]
    Mitotic shape changes drive spatiotemporally segregated cell-contact rearrangements in a proliferating epithelium.
    Subramanian P Ramanathan, Tanmoy Sarkar, Matej Krajnc, Rosemary Mwithiga, Azize Cerci, Chongbei Zhao, Matthew C Gibson.
      In animals, epithelial tissue morphology is determined by the shape, position, and number of its component cells. Nevertheless, it remains incompletely understood how the shape transformations that accompany epithelial mitosis influence tissue packing. Combining an in silico vertex model with live imaging of murine intestinal organoids, we show that mitotic shape changes drive a spatiotemporally segregated sequence of cell-contact rearrangements: basal diminution of mitotic cells, transient multicellular rosette assembly, and reinsertion of the daughter cells. Strikingly, the reinsertion is accompanied by neighbor exchanges oriented perpendicular to the daughter-daughter contact in silico and in organoids, which indicates that reinsertion geometry is sufficient to set the direction of rearrangement. Pharmacological arrest of mitotic progression reveals that basal diminution and daughter reinsertion independently drive distinct contact rearrangements. Together, our results establish that two distinct geometric asymmetries of mitosis, the apico-basal diminution of the dividing cell and the in-plane anisotropy of daughter reinsertion, drive a program of cell rearrangement that reorganizes basal cell-contact topology, thus providing an intrinsic route by which proliferating epithelia accommodate new cells.
    Keywords:  basal rosettes; cell division; cell neighbor exchanges; cell packing; cell shape; cell-contact dynamics; epithelial organization; intestinal organoids; vertex model simulations
    DOI:  https://doi.org/10.1016/j.cub.2026.09.012
  19. Nat Chem Biol. 2026 Sep 30.
    Multiomic proximity labeling in vivo by D-amino-acid-activated peroxidase reaction.
    Jiapeng Liu, Jian Han, Yupu Wang, Mengjiao Song, Jianbei Zhu, Yu Liang, Fangyi Chen, Zhike Liu, Xinwen Yan, Ziyuan Wang, Weicheng Peng, Ruibo Tu, Zihan Zhang, Binglin Zhong, Hao Sun, Junyi Yin, Jingbo Chang, Yuying Long, Yinghui Men, Shang-Jui Tsai, Shanshan Wang, Teodorus Theo Susanto, Albert Qiang, Yong Chen, Weijun Pan, Yizhu Lin, Wei Wu, Yidong Shen, Jiefu Li, Yue Wan, Shuo Han.
      Understanding the spatial organization of biomolecules in living organisms is a central but challenging goal in biology. Here, we introduce peroxidase reactions activated by D-amino acids (PRADA), which uses an engineered oxidase to convert nonproteinogenic D-amino acids into H2O2 for in situ activation of a genetically fused peroxidase. PRADA enables versatile proximity-based chemistries, including protein labeling, RNA labeling and functional polymer assembly, with minimal toxicity and background. We demonstrate that PRADA is broadly applicable inside living organisms, including flies, worms, fish and mice. By further leveraging the unique RNA reactivity of PRADA, we developed a mutational profiling sequencing strategy for spatiotemporally resolved mapping of RNA secondary structure. Application of this multifaceted PRADA platform in a mouse xenograft model offered insights into its mitochondrial proteome, transcriptome and RNA structurome, revealing RNA folding as a regulatory mechanism in mitochondrial gene expression. Collectively, PRADA holds promise to uncover the intricate organization of biomolecules in vivo.
    DOI:  https://doi.org/10.1038/s41589-026-02336-5
  20. bioRxiv. 2026 Sep 24. pii: 2026.09.01.748489. [Epub ahead of print]
    Starvation improves epithelial fitness by selectively extruding DNA damaged cells.
    Lily A Gates, Dustin C Bagley, Konstantinos Kalyviotis, John Fadul, Tania Auchynnikava, Maria Voronkov, Jody Rosenblatt.
      During homeostasis, crowded cells with the lowest energy levels are eliminated by extrusion via Piezo1 signalling to maintain constant cell numbers. However, crowding-induced extrusion does not necessarily remove damaged or otherwise unfit cells. Here, we show that glucose or glutamine starvation triggers a rapid, regulated wave of extrusion, called starvation-induced cell extrusion (STICE), that selectively eliminates cells bearing DNA damage markers via a p53-dependent, Piezo1-independent pathway, improving monolayer fitness. Unlike non-extruding cells, which recycle contents through autophagy and lysosomal digestion, p53-activated cells instead use LC3 to drive lysosomal exocytosis, promoting extrusion signalling. By eliminating defective and transformed cells, STICE confers resistance to damage and apoptotic stimuli in the remaining monolayer. STICE thus acts as a tissue-level analogue of autophagy: rather than improving individual cells by digesting and recycling damaged components, it improves tissue fitness by eliminating substandard cells.
    DOI:  https://doi.org/10.64898/2026.09.01.748489
  21. Nat Chem Biol. 2026 Sep 28.
    SRSF1 modulates the dark nucleolar cap pH to restore nucleolar integrity and function.
    Suibin Ma, Jierui Guo, Xiang Zhan, Fan Wu, Shuo Yang, Chaoqun Huang, Bo Wang.
      The nucleolus is a multiphase condensate with three subcompartments organized by an internal pH gradient. Although pH regulates condensate dynamics and function, how it is controlled under various physiological and pathological conditions remains poorly understood. Here we show that splicing factor SRSF1 is shuttled from nuclear speckles to the dark nucleolar caps (DNCs) under stress that often interrogates nucleolar rRNA synthesis. SRSF1 DNC localization is partially reliant on a molecular interaction with DDX18. Loss of SRSF1 impedes the pH homeostasis of the DNCs and subsequently obstructs the restoration of the nucleolar multiphase and functional recovery from stress. The arginine/serine-rich (RS) domain of SRSF1, due to its high positive charge, is accountable for alkalizing the DNC microenvironment. Interestingly, synthetic arginine-rich dipeptide derivatives of the SRSF1 RS domain safeguard the nucleolus from pH and functional disturbance. Our findings uncover unprecedented mechanistic insights into pH regulation of the nucleolar caps.
    DOI:  https://doi.org/10.1038/s41589-026-02316-9
  22. Nat Nanotechnol. 2026 Sep 28.
    Mechanical stress remodelling drives epithelial-mesenchymal transition in the tumour microenvironment.
    Minji An, Ri Yu, Annie Lin, Jinho Jang, Jiyeon Ohk, Jaemog Jung, Young-Joo Kim, Hosung Jung, Minsuk Kwak, Young-Wook Jun, Jinwoo Cheon.
      The dynamic mechanical response of tissues underlies their physiological function; yet a direct, quantitative measurement of tissue stress in vivo has remained a major challenge. Here we introduce the mechanoMR microparticle sensor, a platform that transduces local tissue mechanical stress into quantitative magnetic resonance read-outs with single-particle resolution. The sensor comprises alginate hydrogel microparticles (~70 μm) homogeneously embedded with Zn0.4Fe2.6O4 magnetic nanoparticles, where stress-induced hydrogel compression reduces local water content and restricts proton diffusion surrounding the magnetic nanoparticles, thereby modulating magnetic-nanoparticle-mediated transverse relaxation (R2). Calibration of the stress-R2 relationship enables a quantitative measurement of local tissue stress over a physiologically relevant range of 0-15 kPa. We demonstrate the platform in tumour spheroids and mouse xenografts, enabling the non-invasive, spatiotemporal mapping of tissue stress during tumour progression. Using this approach, we show that epithelial-mesenchymal transition is accompanied by distinct stress remodelling patterns in vivo. Strikingly, abrupt stress increases, rather than cumulative or peak stress magnitude, determine epithelial-mesenchymal transition induction. Transcriptomic profiling reveals that gradual stress loading activates cytoprotective FOXO/AMPK pathways that reinforce epithelial stability, whereas acute stress surges overwhelm these defence mechanisms, predisposing cells to mesenchymal reprogramming. These findings establish the mechanoMR microparticle sensor as a broadly applicable platform for linking tissue mechanics to cell-state transitions in development and disease.
    DOI:  https://doi.org/10.1038/s41565-026-02282-2
  23. bioRxiv. 2026 Sep 22. pii: 2026.09.18.752733. [Epub ahead of print]
    Zyxin and LPP differ in their sensing of strained actin filaments at tricellular junctions.
    Katherine K Tjoelker, Tamsuk Paul, Babli Adhikary, Yashar Bashirzadeh, Sahithya S Iyer, Kristina M Herman, Leah M Beel, Lijuan Xing, Gregory A Voth, Allen P Liu, Ann L Miller.
      The actomyosin cytoskeleton plays important roles in cell-cell adhesion by generating and responding to forces. Actin-binding proteins support actomyosin networks by reinforcing actin filaments, promoting actin remodeling, and transmitting forces to transmembrane adhesion proteins. One family of actin-binding proteins, LIM domain-containing proteins, is recruited to strained actin filaments. Here, we investigate two members of the LIM domain family, Zyxin and Lipoma-Preferred Partner (LPP), using the embryonic epithelium of Xenopus laevis , where actin-associated cell-cell junctions connect cells to promote tissue integrity and barrier function. Specifically, we compare Zyxin and LPP's response to increased tension at tricellular junctions (TCJs), sites of heightened mechanical strain within the tissue. Upon increased tension, Zyxin and LPP mechanoaccumulate to different extents relative to F-actin, suggesting distinct mechanisms. Our results demonstrate that Zyxin's and LPP's LIM domain-containing regions (LCRs) are sufficient for mechanoaccumulation as well as responsible for the difference in mechanoaccumulation, while their N-termini play a regulatory role in their mechanosensitive responses. Docking simulations show that a hydrophobic interaction between the LCR and the "crack site" that forms in F-actin filaments under high force may underlie the LCR's sensing of strained F-actin. Additionally, the docking simulations reveal that previously-identified conserved residues are present at the binding interface. Mutations of conserved residues in Zyxin or LPP reduce the extent of mechanoaccumulation at TCJs, supporting the docking prediction. Together, this study advances our understanding of Zyxin and LPP's sensing of strained actin at TCJs under mechanical challenge.
    Significance Statement: The actomyosin cytoskeleton provides structural support for intercellular connections. This is particularly important at high force levels when actin must be reinforced by actin-binding proteins. Two of those proteins, Zyxin and LPP, stabilize strained actomyosin networks. Using frog embryos, we compare the force-dependent recruitment of these proteins at cell-cell junctions where three cells meet. Despite their similar sequences, Zyxin and LPP respond differently to increased tension. We find that the LIM-domain-containing region (LCR) confers this force-sensing behavior for strained actin at cell-cell junctions. The rest of the protein regulates the extent to which the proteins accumulate. Computational modeling suggests that the accumulation difference between Zyxin and LPP may be due to variations in the LCR and strained actin-binding interface.
    DOI:  https://doi.org/10.64898/2026.09.18.752733
  24. Nat Struct Mol Biol. 2026 Oct 02.
    Single-molecule chromatin tracing reveals a diversity of megabase heterochromatin domains.
    Dania Camila Pulido-Barrera, Jia E You, Angelo L Angonezi, Alexander Kuznetsov, Fei Xu, Tobias Verheijen, Ahilya N Saw, Pavel Kos, Luca Giorgetti, Nacho Molina, David Brückner, Susan E Mango.
      Chromosomes fold into distinct domains that regulate transcription, replication and repair. In addition to well-characterized topologically associating domains (TADs) and compartments, the diversity of heterochromatin domains remains poorly defined at the sequence level. Here, using single-molecule tracing of nascent heterochromatin in Caenorhabditis elegans, we identify three classes of megabase-scale domains: (1) sharp-boundary, condensin I-dependent TAD-like domains (TADLs), which arise before zygotic genome activation; (2) similarly sized, but condensin-independent, elegans condensin-independent domains (elCIDs), one of which encompasses the 5S-spliced leader repeat locus; and (3) decompacted, diffuse structures that are abundant in the population but probably missed by crosslinking assays. Condensin I sits at the border of the TADL domain, whereas DNA-binding proteins, active histone marks and maternally active genes flank the elCID domains, suggesting that boundaries are established by distinct mechanisms for different types of domains. Our results uncover previously unrecognized heterochromatin architectures and implicate maternal transcriptional activity in shaping domain boundaries in early embryos in C. elegans.
    DOI:  https://doi.org/10.1038/s41594-026-01895-4
  25. Semin Cell Dev Biol. 2026 Sep 30. pii: S1084-9521(26)00021-2. [Epub ahead of print]185-187 103687
    Squamous epithelial morphogenesis and mechanobiology across the lifetime of dynamic barrier tissues.
    Kristen A Panfilio, Juan Manuel Gomez.
      Barrier epithelia perform crucial protective and regulatory roles, with their development occurring in careful coordination with the tissues that they enclose. Many barrier epithelia are transient tissues with precise mechanisms of morphogenesis on spatial scales spanning over an order of magnitude, encompassing both early transitions to a squamous shape and wholesale remodeling at the end of the tissue's lifetime. Here, we compare exemplar tissues from Drosophila, Tribolium, and other insects: the extraembryonic, larval epidermal, peripodial, and follicular epithelia. We consider the extent to which these tissues share key structural features - such as a switch to the endocycle, secretion of an apical extracellular matrix, and apoptosis - and their implications for morphogenesis and physical interactions with other tissues. We also explore the process of becoming squamous from diverse precursor cell states, with the goal of identifying mechanistic commonalities. We emphasize the role of vesicle trafficking and cell adhesion remodeling at the cell-autonomous level, and we discuss the putative instructive role of mechanical forces as non-tissue-autonomous inputs in squamous shape acquisition. Further, we evaluate the time-evolution of cell deformability during squamous morphogenesis, measured with Brillouin microscopy, an emerging optical tool that maps material properties (e.g., stiffness) of cells and tissues of intact organisms in 4D. Finally, we examine the extent to which epithelial cell shape can be reversible during end-stage morphogenesis. Our comparative approach highlights general principles and open questions on the emergent properties of transient, squamous epithelia.
    Keywords:  Amnion; Apical-basal polarity; Brillouin microscopy; Cytoskeleton; Mechanobiology; Serosa; Tissue interactions
    DOI:  https://doi.org/10.1016/j.semcdb.2026.103687
  26. Circulation. 2026 Sep 29. 154(13): 1261-1264
    Modeling Heart Failure With Preserved Ejection Fraction Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
    Brian Yu, Lu Ren, Yu Liu, Chengyi Tu, Ana Kojic, Yuanyuan Dai, Ravichandra Venkateshappa, Mengcheng Shen, Shane R Zhao, Joseph C Wu.
      
    Keywords:  diastole; heart failure, diastolic; induced pluripotent stem cells; myocytes, cardiac; organoids
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.126.081881
  27. Science. 2026 Oct;394(6819): eaed3065
    Loss of the tumor suppressor p53 generates a signaling gradient that drives epithelial clonal expansion.
    Qiwen Gan, Wei Li, Rachel K Lex, Zhe Ying, Slobodan Beronja.
      Although tumor protein p53 (TP53) mutations are among the most common lesions in epithelial cancers, how p53 loss drives unrestrained clonal expansion remains unclear. Working with mouse epidermis, we found that p53 suppresses clonal expansion by limiting progenitor self-renewal. Integrating chromatin immunoprecipitation sequencing, transcriptional analyses, and genetic screens, we identified a p53-dependent network controlling progenitor renewal and differentiation, in which secreted frizzled-related protein 1 (Sfrp1), low-density lipoprotein receptor-related protein 1 (Lrp1), and ubiquitin-specific peptidase 22 (Usp22) were direct targets of p53 and the most genetically upstream components. Their suppression after p53 loss generated a radial gradient of Wnt activity across mutant clones. Genetic manipulation showed that a Wnt activity gradient, rather than uniform elevation, was associated with sustained clonal expansion. These findings identify spatial organization as a determinant of clonal behavior and a mechanism by which TP53 inactivation drives tissue colonization.
    DOI:  https://doi.org/10.1126/science.aed3065
  28. Nature. 2026 Oct;658(8134): 45-54
    Written in development and lost in ageing: the grammar of cellular identity.
    A Doğa Yücel, Adrian Molière, Vadim N Gladyshev.
      Ageing has been described through many theoretical frameworks, yet its mechanistic basis remains unresolved. Here we propose that ageing reflects progressive decanalization of mammalian cell identity, driven by erosion of a regulatory grammar written during development. Extending Waddington's epigenetic landscape, development canalizes cell fates through globally coordinated chromatin programs that establish identity constraints across multiple timescales. Subsequently, these constraints can only be maintained through local mechanisms with limited fidelity. The asymmetry between high-fidelity writing and imperfect maintenance generates predictable drift that accumulates with biological time. Antagonistic chromatin pathways, particularly polycomb repressive complex 2 (PRC2)-mediated repression opposed by H3K4/36 methylation and RNA polymerase II binding, enforce identity boundaries through mutual constraint. With age, this balance erodes. Consistent with this framework, the vast majority of age-associated DNA methylation gain in somatic mitotic tissues occurs at PRC2-bound low-methylated regions, indicating that these domains function as conserved coordinates of slow-layer drift. This model explains cross-tissue ageing signatures, developmental timing-to-lifespan correlations and robustness of pan-mammalian epigenetic ageing clocks. It provides testable predictions for interventions that stabilize architecture to preserve cellular identity and function.
    DOI:  https://doi.org/10.1038/s41586-026-10955-0
  29. Nat Struct Mol Biol. 2026 Sep 30.
    A phosphoproteome atlas of human cell lines reveals the landscape of kinase activity.
    Claire Koenig, Hayoung Cho, Kristina B Emdal, Ilaria Piga, Pierre Sabatier, Samuel Lozano-Juárez, Ana Martinez-Val, Jesper V Olsen.
      Protein phosphorylation orchestrates cellular signaling and controls most biological processes, with its dysregulation driving diseases, notably cancer. Comprehensive, high-throughput phosphoproteomics remains limited by detection sensitivity, data completeness and computational bottlenecks, especially in low-input settings. Here we present a comprehensive empirical human phosphoproteome resource, regrouping over 200,000 class I phosphosites across 33 diverse human cell lines. We demonstrate that this spectral library dramatically improves single-shot phosphoproteomics with 30-fold faster data processing compared with library-free approaches and enhances confidence in phosphosite localization even from minimal sample input. Integrating proteome and phosphoproteome data, we develop a combined kinase activity score (Cscore), revealing cell line- and cancer-specific signaling vulnerabilities, many correlating with drug sensitivity. This resource accelerates deep and reproducible phosphoproteomics, enables the systematic mapping of cellular signaling networks and may empower precision oncology by highlighting actionable kinase targets in diverse cell states.
    DOI:  https://doi.org/10.1038/s41594-026-01877-6
  30. Mol Cell. 2026 Sep 29. pii: S1097-2765(26)00628-3. [Epub ahead of print]
    The early RNA decay factor ZC3H18 directs first intron splicing.
    Marion Le Rest, Nour El Houda Benbahouche, Christopher Cyrus Kuhn, Jérôme Rouvière, Lis Jakobsen, Marie-Cécile Robert, Julie Abrino, Om Rathore, Yujia Zhang, Andrii Bugai, Céline Verheggen, William Garland, Jens S Andersen, Elena Conti, Edouard Bertrand, Torben Heick Jensen.
      Pre-mRNA splicing is essential for gene expression. In human cells, the cap-binding complex (CBC) has long been known to facilitate first intron splicing, but it is by an unknown mechanism. The CBC also promotes early RNA decay by recruiting the nuclear exosome targeting (NEXT) complex via the linker proteins ARS2 and ZC3H18. How the CBC orchestrates these opposite activities is elusive. Here, we show that ZC3H18 interacts with three splicing factors, PRPF40A, PRP4K, and FNBP4, to stimulate first intron splicing genome wide. Linking this unexpected function of ZC3H18 to the CBC, disruption of the CBC-ARS2-ZC3H18 axis corrupts first intron splicing. Although ZC3H18 acts in both RNA decay and splicing, its association with splicing factors is mutually exclusive with its binding to NEXT. Our results rationalize cap-stimulated first intron splicing mechanistically and suggest that splicing factors displace NEXT from ZC3H18, designating the nascent RNA to a productive pathway at the expense of RNA decay.
    Keywords:  ARS2; CBCA complex; PRPF40A; ZC3H18; cap-dependent splicing; early RNA decay; first intron splicing
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.009
  31. Elife. 2026 Oct 01. pii: RP108588. [Epub ahead of print]14
    Bidirectional redistribution of actomyosin drives epithelial invagination in ascidian siphon tube morphogenesis.
    Jinghan Qiao, Pengyu Yu, Hongzhe Peng, Wenjie Shi, Bo Li, Bo Dong.
      How epithelia perform a spatiotemporal heterogeneous force-generating program to drive a sequential tissue morphogenesis remains unclear, particularly the underlying precise mechanical mechanisms. This study investigated dynamic actomyosin reorganization between apical and lateral membrane cortex regions during two sequentially invaginated stages of atrial siphon tube morphogenesis in the ascidian Ciona. At the initial invagination stage, the originally lateral-located actomyosin redistributed to the apical domains, while that actomyosin redistributed back to lateral domains at the accelerated invagination stage. Using genetic mutants to modulate myosin activities, the initial invagination was strengthened or abolished, indicating invagination is apical constriction-dependent. Optogenetic inhibition of myosin activities in lateral domains after initial invagination stage blocked the further processes, suggesting lateral constriction of actomyosin is required for the accelerated invagination. Vertex model simulations uncovered a coupled mechanism underlying epithelial invagination driven by apicobasal tension imbalance and lateral contraction. We thus propose an actomyosin redistribution mechanical model: lateral actomyosin first redistributes apically to drive apical constriction and shape the initial invagination, then apical actomyosin redistributes laterally to promote lateral contractility and accelerate invagination. Our findings reveal a bidirectional reorganization of the actomyosin network as a central mechanism driving epithelial invagination, providing insights on epithelial invagination and organ morphogenesis during development.
    Keywords:  C. intestinalis; Ciona; actomyosin; atrial siphon; developmental biology; epithelial invagination; redistribution; vertex model
    DOI:  https://doi.org/10.7554/eLife.108588
  32. Nat Struct Mol Biol. 2026 Sep 28.
    HERC4-mediated ubiquitination licenses RIPK1 to initiate TNF-induced cell death.
    Haohao Lu, Tongde Du, Lin Li, Dongmei Cao, Ke Li, Linjie Liu, Rui Li, Xiaoliang Yu, Shouqiao Hou, Xinhui Wang, Minyan Shi, Yanfen Liu, Feng Ma, She Chen, Henning Walczak, Sudan He.
      TNF can activate both prosurvival and prodeath signaling downstream of tumor necrosis factor receptor 1 (TNFR1). Survival signaling originates from TNFR1-containing membrane-bound complex I, while death signaling is driven by cytosolic complex II. Receptor-interacting protein kinase 1 (RIPK1) is a central component of both complexes but the molecular switch converting RIPK1 from a prosurvival scaffold in complex I to a prodeath kinase in complex II has remained elusive. Here, we identify the E3 ligase HERC4 as the molecular determinant of prodeath signaling. We show that HERC4 binds complex I-derived S166-phosphorylated, kinase-active RIPK1 and ubiquitinates it within its death domain. This enables RIPK1 oligomerization and assembly of the apoptosis-inducing RIPK1-FADD-caspase 8-containing complex IIa and, upon caspase inhibition, formation of the necroptosis-initiating RIPK1-RIPK3-containing necrosome. HERC4 deficiency protects mice from TNF-induced systemic inflammatory response syndrome and acute liver injury. Thus, HERC4 is the link enabling complex I-derived RIPK1 to initiate death signaling.
    DOI:  https://doi.org/10.1038/s41594-026-01871-y
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