bims-ginsta Biomed News
on Genome instability
Issue of 2026–08–30
38 papers selected by
Jinrong Hu, National University of Singapore
  1. Elevated contractility drives implantation failure in mouse embryos from aged females.
  2. A transient RNP compartment boosts translation and growth of mammalian oocytes.
  3. CDC7 and APC/CCdh1 gate distinct routes to initiate DNA replication.
  4. Mammalian metaphase kinetochores are elastic and require condensin for robust structure and function.
  5. De novo E-cadherin/catenin complex formation controls basal epithelial mechanics and force transmission for apoptotic cell clearance.
  6. Mechanisms of MCM2-7 helicase activation and initial DNA melting at near base-pair resolution.
  7. Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.
  8. Integrative spatial profiling of 3D genome organization and gene expression in tissue.
  9. Goblet cells mechanically breach the epithelial barrier in gut homeostasis.
  10. BLTP2 bridges the ER and MVB for exosome biogenesis at SCAMP3-dependent ER contacts.
  11. cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
  12. Loss of Nemp1 disrupts female meiosis and activates a conserved ATM-CHK2 checkpoint.
  13. The proportional scaling of mRNA and ribosome concentrations controls eukaryotic cell growth.
  14. DDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain development.
  15. Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
  16. Cell cycle-dependent translation-mediated turnover of the long noncoding RNA Malat1.
  17. SGLT2 inhibitors activate pantothenate kinase in the human heart.
  18. Mitotic single-stranded DNA suppression by DDIAS.
  19. Tcf15 promotes an open nucleolar chromatin state to safeguard ribosome biogenesis and genome stability in mouse embryonic stem cells.
  20. Predictive design of tissue-specific mammalian enhancers that function in the mouse embryo.
  21. Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.
  22. Prefoldin function links meiotic chromosome segregation with cellular remodeling and reveals tubulin sensitivity of the meiotic spindle.
  23. A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
  24. Mitochondrial DNA leakage in oocytes activates cGAS-STING signaling to drive ovarian aging.
  25. Zinc increases stress granule formation by promoting RNA condensation.
  26. The R-loop-SPT6-SETD2 axis safeguards H3K36me3 to prevent broad H3K4me3 invasion in mouse oocytes.
  27. A STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity.
  28. Antibody Fc receptor CD16a mediates natural killer cell activation via mechanotransduction of piconewton forces.
  29. In situ mapping of late-stage biomechanical coordination during clathrin-mediated endocytosis.
  30. Dysregulated differentiation kinetics underlie the essential role of DNA damage repair in placental development.
  31. Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
  32. State-dependent binding of the wedge domain controls inactivation of the mechanosensitive ion channel PIEZO1.
  33. Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.
  34. Zasp52's differentially expressed intrinsically disordered region confers thin filament stability at the Z-disc.
  35. Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease.
  36. HoT auto-blinking probes enable real-time, super-resolution chromatin imaging in live cells and tissues.
  37. Insulin-like growth factor-binding protein 7 is a soluble cell adhesion molecule.
  38. Condensation of MATCAP promotes CENP-E-dependent chromosome congression in mitosis.
  1. Nat Cell Biol. 2026 Aug 25.
    Elevated contractility drives implantation failure in mouse embryos from aged females.
    Kate E Cavanaugh, M J Franco-Oñate, Nicole Horsley, Dilan Gokyer, Tomiris Atazhanova, Diana J Laird, Patrick W Oakes, Joan K Riley, Francesca E Duncan, MaryEllen Pavone, Matteo Molé, Ricard Alert, Orion D Weiner.
      Women in their mid-30s experience a marked decline in fertility. The origin of these fertility defects resides in the implantation capacity of the embryo itself, but the mechanistic basis of this impairment is not well understood. Here we identify a core mechanical defect in embryos from aged females that impairs their implantation competence. Using mouse models, we find that reproductive ageing drives excessive contractility in the trophectoderm, the outer epithelial lineage that enables implantation. This hypercontractility increases blastocyst tissue surface tension and viscosity, which hinders spreading during implantation. Elevated contractility is both necessary and sufficient for age-associated implantation failure. We identify non-invasive imaging signatures that infer embryo mechanics and predict implantation success for embryos of both young and aged females. Analyses of human embryos and in vitro fertilization clinical datasets reveal conserved age-associated mechanical alterations that correlate with implantation potential. Our work implicates embryo mechanics as a key regulator of reproductive longevity.
    DOI:  https://doi.org/10.1038/s41556-026-02052-1
  2. Sci Adv. 2026 Aug 28. 12(35): eaej5359
    A transient RNP compartment boosts translation and growth of mammalian oocytes.
    Noemi Zollo, Gabriele Zaffagnini, Ali Haidar, Alexis Canette, Gaëlle Letort, Christelle Da Silva, Elsa Labrune, Nicolas Tessandier, Julien Dumont, Corinne Blugeon, Benoit Wattellier, Elvan Böke, Christopher Thomas, Maria Almonacid, Marie-Hélène Verlhac.
      Mammalian oocytes undergo an extended growth phase, during which transcription gradually declines. To sustain meiotic divisions and early embryonic development, growing oocytes must accumulate maternal stores and tightly regulate translation. Using immunofluorescence, mass spectrometry, electron microscopy, RNA sequencing, and live ex vivo ovarian tissue-slice imaging, we identified a transient ribonucleoprotein-organelle compartment in growing mouse oocytes, which we named the Zollo body. Although it resembles the Balbiani body observed in nongrowing oocytes of many vertebrate species, the Zollo body arises during growth and shows nascent translation and phospho-mTOR enrichment. Pharmacological dissolution of the Zollo body arrests follicle and oocyte growth in cultured ovarian tissue slices. Thus, the Zollo body is a transient, translation-associated compartment required for normal follicle and oocyte growth.
    DOI:  https://doi.org/10.1126/sciadv.aej5359
  3. Nat Commun. 2026 Jul 24. pii: 9016. [Epub ahead of print]17(1):
    CDC7 and APC/CCdh1 gate distinct routes to initiate DNA replication.
    Samsara W Upadhya, Nalin Ratnayeke, Katherine R Ferrick, David L Rosenthal, Tobias Meyer.
      Precise temporal control of DNA replication initiation is essential for faithful cell division, yet there are conflicting prevailing models for how cells trigger origin firing. Here, we demonstrate that human origins are not fired at fixed thresholds of cell cycle regulators E2F, APC/CCdh1, CDK2/1, and CDC7. Instead, origin firing is triggered at a tunable CDK2/1 threshold that is gated by either CDC7 or APC/CCdh1 activity. CDC7 phosphorylates MCM helicase, enabling Cyclin E-CDK2 to trigger origin firing at low CDK2/1 activity, independent of APC/CCdh1 inactivation. In contrast, APC/CCdh1 inactivation enables Cyclin A-CDK1 to phosphorylate MCM at distinct CDK2/1-specific sites and trigger origin firing, independent of CDC7 activity. Strikingly, this requires much higher CDK2/1 activity, which CDK2 cannot normally reach alone. Thus, having two distinct routes necessitates blocking both routes to prevent S phase: either by inhibiting CDC7 or CDK2 while also preventing APC/CCdh1 inactivation or inhibiting CDK1.
    DOI:  https://doi.org/10.1038/s41467-026-75804-0
  4. J Cell Biol. 2026 Oct 05. pii: e202512154. [Epub ahead of print]225(10):
    Mammalian metaphase kinetochores are elastic and require condensin for robust structure and function.
    Vanna M Tran, Jinghui Tao, Caleb J Rux, David Gomez Siu, Miquel Rosas-Salvans, Sophie Dumont.
      The mammalian kinetochore connects chromosomes to dynamic spindle microtubules. To remain attached, it must maintain structural integrity under force, but to what extent and how it does so remain unclear. Under spindle forces, we find using super-resolution microscopy that inner (CENP-A) and outer (Hec1) metaphase kinetochores undergo correlated, large-scale (1 µm) deformations along the force axis, suggesting dynamic, relative sliding of parallel protein linkages. Kinetochore shape changes can be asymmetric, with centromere-facing "tails" correlating with hyperstabilized microtubule attachments. Applying microneedle pulling forces, we demonstrate that kinetochores are elastic, stretching under force and relaxing in seconds afterward. Finally, we show that SMC2 depletion results in more variable kinetochore deformations, despite maintained elasticity, and in reduced microtubule attachment stability. Thus, the kinetochore is structurally highly dynamic, requiring a stable centromere base to maintain structure and function under force. We propose a model whereby individual protein linkages are stiff, yet global kinetochore structure is flexible to accommodate different attachment geometries and forces while maintaining function.
    DOI:  https://doi.org/10.1083/jcb.202512154
  5. Nat Commun. 2026 Aug 27. pii: 8900. [Epub ahead of print]17(1):
    De novo E-cadherin/catenin complex formation controls basal epithelial mechanics and force transmission for apoptotic cell clearance.
    Hanna-Maria Häkkinen, Marta Batet, Laura F Bianchi, Senda Jiménez-Delgado, Fabio Pezzano, Stefan Wieser, Luca Ciampa, Esteban Hoijman, Carina Vibe, Sofie Wijma, Verena Ruprecht.
      Beyond serving as cohesive barriers, epithelia clear apoptotic cells to regulate development, homeostasis and inflammation. How epithelial cells remodel their shape during phagocytosis while preserving tissue integrity, and the role of adhesion receptors in this process, remain unclear. Using live in vivo imaging of phagocyte-target interactions in zebrafish (Danio rerio) embryos, we show that basal and apical epithelial domains are mechanically decoupled, enabling engulfment without disrupting tissue cohesion. We identify a dynamic assembly of E-cadherin/catenin complexes at the basal epithelial surface in contact with apoptotic cells. Targeted perturbations reveal two critical functions of de novo E-cadherin/catenin complex formation at the phagocytic synapse: α-catenin acts as a physical linker transmitting actin-generated forces required for engulfment, while p120-catenin restrains Myosin II activity, enabling efficient clearance. We further demonstrate the conservation of E-cadherin-dependent apoptotic cell clearance in the mouse trophectoderm. These findings reveal that the E-cadherin/catenin complex is repurposed at the phagocytic synapse as a mechano-regulator of epithelial efferocytosis beyond its canonical role in tissue cohesion.
    DOI:  https://doi.org/10.1038/s41467-026-76710-1
  6. Nat Commun. 2026 Jul 23. pii: 8984. [Epub ahead of print]17(1):
    Mechanisms of MCM2-7 helicase activation and initial DNA melting at near base-pair resolution.
    Christopher Weekes, Lia Willerding, Sanjay P Khadayate, Korbinian Liebl, Audrey Mossler, Alex Montoya, Vanessa Rauthe, Mohammad M Karimi, Martin Zacharias, Helle D Ulrich, Christian Speck, L Maximilian Reuter.
      During eukaryotic DNA replication initiation, inactive MCM2-7 double-hexamers assembled at replication origins must be converted into two active CMG helicases, yet how this transition is coupled to origin DNA unwinding in vivo remains unclear. Here, we identify a DNA-bound intermediate with an extended genomic footprint that forms during helicase activation. Genome-wide mapping of initial strand separation reveals that DNA unwinding initiates near the N-terminal interface of opposing MCM2-7 hexamers. At these sites, the origin DNA exhibits a conserved AT-rich/GC-rich/AT-rich sequence architecture centred under the helicase complex, which is associated with an elevated DNA melting probability. We further show that restricting hexamer splitting delays release of the Cdc45-loading factor Sld3, demonstrating that mechanical transitions during helicase activation are tightly coupled to complex disassembly. Finally, we provide in vivo evidence that single-stranded DNA is ejected through a specialised DNA exit gate at the Mcm2/5 interface during helicase activation, which is dispensable for ongoing DNA synthesis. Together, these findings establish a mechanistic framework for how replication origins are remodelled to initiate DNA replication and reveal key intermediates and DNA transactions during helicase activation.
    DOI:  https://doi.org/10.1038/s41467-026-75695-1
  7. Dev Cell. 2026 Aug 28. pii: S1534-5807(26)00290-X. [Epub ahead of print]
    Senescent cells maintain viability through adhesion-dependent fragmentation that promotes debris deposition.
    Matej Durik, Mona Karout, Daniel Sampaio Gonçalves, Tania Knauer-Meyer, Coralie Spiegelhalter, Nadia Messaddeq, Marco Seehawer, Pauline Stephan, Dmitry V Bulavin, Yann Herault, Lars Zender, William M Keyes.
      Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here, we identify that senescent cells dispose of large fragments through cell-to-cell adhesion, which we term "senescent-cell adhesion fragments" (SCAFs). Found in many senescent states, including human and mouse cells, and mouse tissues, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreases SCAF formation but induces senescent-cell death, due to an inability to shed damaged mitochondria. Live imaging and proteomics show that SCAFs ultimately rupture, releasing a complex proteome, including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Immunostaining also reveals amyloid-like material in senescent cells that can be externalized through fragmentation. Altogether, these findings identify a feature that facilitates senescent cell survival but also externally deposits damaged intracellular contents, with implications for cancer and neurodegeneration.
    Keywords:  DAMPs; aging; amyloid; cancer; cell-cell adhesion; debris; mitochondria; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2026.08.002
  8. Cell. 2026 Aug 25. pii: S0092-8674(26)00871-8. [Epub ahead of print]
    Integrative spatial profiling of 3D genome organization and gene expression in tissue.
    Pengfei Guo, Yan Cui, Jincan He, Abraham J Waldman, Jiaxin Zhu, Yufan Chen, Zhi Huang, Jingtian Zhou, Jennifer E Phillips-Cremins, Yanxiang Deng.
      Three-dimensional genome organization shapes transcriptional regulation, yet measuring its spatial coordination in situ within intact tissues remains challenging. We present Spatial Hi-C-RNA, a multimodal platform that simultaneously maps genome-wide chromatin contacts and transcriptomes from the same tissue section at near-single-cell resolution. Across the mouse brain, developing embryos, and human melanoma, Spatial Hi-C-RNA generated multimodal maps that aligned with tissue anatomy while revealing complementary chromatin- and RNA-defined spatial patterns. Multiscale features, including A/B compartments, topologically associating domains, and chromatin loops, were associated with region- and cell-type-specific transcriptional programs. In mouse embryos, Spatial Hi-C-RNA resolved coordinated chromatin and transcriptional remodeling during neuronal maturation across developmental stages. In human melanoma, chromatin architecture delineated intratumoral subregions not detected by RNA alone and linked tumor-state transitions to changes in compartments, domain boundaries, and regulatory programs. Spatial Hi-C-RNA thus provides a broadly applicable framework for investigating genome structure-function relationships in development and disease within native tissue environments.
    Keywords:  3D genome; A/B compartments; Spatial Hi-C; chromatin remodeling; chromosome conformation capture; gene regulation; neuroepigenetics; neurogenesis; spatial multi-omics; spatial transcriptomics; tumor-state transitions
    DOI:  https://doi.org/10.1016/j.cell.2026.07.039
  9. Nat Commun. 2026 07 25. pii: 9078. [Epub ahead of print]17(1):
    Goblet cells mechanically breach the epithelial barrier in gut homeostasis.
    Justine Creff, Yuan He, Sandra Bernat-Fabre, Etienne Buscail, Salomé Neuvendel, Vishnu Krishnakumar, Dhriti Saumya, Laurent Malaquin, Thomas Mangeat, Shi-Lei Xue, Denis Krndija.
      The intestinal epithelium forms a tight barrier against the harsh luminal environment. Absorptive enterocytes have a polygonal, columnar morphology, while mucus-producing goblet cells exhibit a rounded apical shape and a voluminous cell body, raising the question of how epithelial integrity is preserved in tissues with such morphological heterogeneity. Here, we show that, under homeostatic conditions in vivo, goblet cells mechanically induce tight-junction fractures between neighboring enterocytes. This effect is exacerbated by goblet cell hypertrophy and is associated with increased gut permeability. Using in vivo and organoid models, combined with pharmacological, genetic and mechanical perturbations and theoretical modeling, we demonstrate that these fractures arise from a force imbalance at cell interfaces: goblet cells exert pressure on adjacent enterocytes, whose junctional rupture depends on tissue rheology controlled by myosin II. Our findings uncover a mechanical role for goblet cells in epithelial cohesion and barrier regulation, revealing how cellular heterogeneity shapes tissue integrity.
    DOI:  https://doi.org/10.1038/s41467-026-76034-0
  10. Curr Biol. 2026 Aug 24. pii: S0960-9822(26)00997-8. [Epub ahead of print]
    BLTP2 bridges the ER and MVB for exosome biogenesis at SCAMP3-dependent ER contacts.
    Jingru Wang, Dongchen Li, Yazhou Liu, Tiantian Zhou, Lin Deng, Wei-Ke Ji.
      Multivesicular bodies (MVBs) contain intraluminal vesicles (ILVs) designated for degradation in lysosomes or release as exosomes for cell-to-cell communication. The mechanisms governing ILV/exosome formation are not fully understood. Here, we show that the integral endoplasmic reticulum (ER) membrane protein bridge-like lipid transfer protein 2 (BLTP2; KIAA0100) is indispensable for ILV/exosome formation and that secretory carrier membrane protein 3 (SCAMP3) recruits BLTP2 to ER-MVB membrane contact sites (MCSs) in a Rab5-dependent manner. Our results indicate that this recruitment is hindered by NEDD4-mediated ubiquitination of SCAMP3. Depletion of BLTP2 was found to impede ILV/exosome formation and selectively reduce the levels of cone-shaped phospholipids, including bis(monoacylglycero)phosphate (BMP), and of the BMP precursor phosphatidylglycerol (PG) within endosomes. BLTP2 knockout also hampered cell proliferation and tumorigenicity, which could be restored by supplementation with exosomes from wild-type cells. Our findings suggest that BLTP2 transfers the BMP/lysobisphosphatidic acid (LBPA) precursor PG to MVBs for BMP/LBPA synthesis and promotes ILV/exosome formation at SCAMP3-dependent ER-MVB MCSs.
    Keywords:  ER; LBPA/BMP; MVB; bridge-like lipid transfer protein; exosome; membrane contact sites
    DOI:  https://doi.org/10.1016/j.cub.2026.07.066
  11. Nat Aging. 2026 Aug 25.
    cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
    John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova.
      Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.
    DOI:  https://doi.org/10.1038/s43587-026-01206-y
  12. Nat Commun. 2026 07 24. pii: 9100. [Epub ahead of print]17(1):
    Loss of Nemp1 disrupts female meiosis and activates a conserved ATM-CHK2 checkpoint.
    Bilal Ahmad Hakim, Yonit Tsatskis, Ling Zhang, Esther Choi, Ying Zhang, Didier Hodzic, Que Wu, MuYun Zhang, Maryam Pashaei, Kyungwon Ha, Jannette Rusch, Julie A Brill, Miguel Angel Brieño-Enríquez, Andrea Jurisicova, Helen McNeill.
      Female germ cells must preserve the integrity of their genome and generate genetic diversity via meiotic recombination. This challenging process is error prone. Highly conserved checkpoint pathways detect errors in recombination and DNA damage, inducing the death of defective oocytes. Nuclear Envelope Membrane Protein (NEMP) homologs are highly conserved proteins critical for fertility in flies, worms, fish and mice. They localize to the inner nuclear envelope where they provide mechanical support. However, why NEMP homologs are specifically required for fertility is still unclear. Using both Drosophila and mouse models, we establish that loss of NEMP homologs leads to activation of ATM and CHK2 kinases and inhibition of CHK2 or ATM rescues oocyte loss. In the absence of Nemp1, meiotic progression is delayed and DNA damage is increased at zygonema and pachynema stages. Loss of Nemp1 also leads to defects in chromosome synapsis persisting through pachynema. We conclude that NEMP1 is needed to protect genome integrity and is crucial for accurate chromosome pairing and synapsis, supporting oocyte developmental competence and survival.
    DOI:  https://doi.org/10.1038/s41467-026-75874-0
  13. Nat Cell Biol. 2026 Aug 25.
    The proportional scaling of mRNA and ribosome concentrations controls eukaryotic cell growth.
    Xin Gao, Michael Lanz, Rosslyn Grosely, Jonas Cremer, Joseph Puglisi, Jan M Skotheim.
      Cell growth underlies nearly all eukaryotic physiology, yet its quantitative principles remain unclear. Here, using single-molecule ribosome tracking, spike-in RNA sequencing and quantitative proteomics across 15 nutrient-limited conditions in budding yeast, we define how growth is controlled in the budding yeast Saccharomyces cerevisiae. Ribosome concentration scales linearly with growth rate, while peptide elongation speed remains constant at approximately nine amino acids per second. While elongation is not a regulatory lever, total mRNA concentration increases proportionally with ribosomes to accelerate growth. A simple kinetic model of mRNA-ribosome binding accurately predicts the fraction of active ribosomes, growth rate and responses to transcriptional or size perturbations. Consistent with this model, transient inhibition of mRNA degradation boosts growth by elevating mRNA concentration. These results reveal that eukaryotic cells accelerate proliferation primarily by proportionally scaling mRNA and ribosome abundance, establishing a quantitative framework for understanding eukaryotic biosynthesis.
    DOI:  https://doi.org/10.1038/s41556-026-02045-0
  14. Cell. 2026 Aug 24. pii: S0092-8674(26)00873-1. [Epub ahead of print]
    DDIAS shields single-stranded DNA in mitosis and promotes vertebrate brain development.
    Kaima Tsukada, Liudmyla Lototska, Aya Tsukada, Menachem V K Sarusie, Ipek Ilgin Gönenç, Charlotte Sherlaw-Sturrock, Manil Kanade, Matous Palek, Antony W Oliver, Samuel E Jones, Satpal S Jhujh, Julius Bannister, Asmat Ali, Muhammad Raza, Mathias Toft, Zafar Iqbal, Ambrin Fatima, Thomas C R Miller, Lars Allan Larsen, Grant S Stewart, Fena Ochs, Andrew N Blackford.
      DNA double-strand breaks and unresolved DNA replication intermediates are particularly dangerous during mitosis. Paradoxically, cells inactivate canonical DNA repair mechanisms during chromosome segregation in favor of alternative pathways that depend on TOPBP1 and CIP2A, but how these pathways function is still poorly defined. Here, we describe the identification of DDIAS as a mitosis-specific DNA damage response protein. We establish DDIAS as a phosphorylation-dependent component and effector of the TOPBP1-CIP2A complex, and we demonstrate that DDIAS protects single-stranded DNA from aberrant nucleolytic processing to safeguard chromosome integrity during mitosis, particularly in BRCA1-/BRCA2-deficient cells. We also identify biallelic inactivating mutations in DDIAS in patients with a severe neurodevelopmental disorder and, using human cerebral organoids and zebrafish, we show that DDIAS plays a critical and evolutionarily conserved role in limiting DNA damage specifically in neural progenitor cells. These findings demonstrate a physiological role for the DNA damage response in mitosis during vertebrate neurodevelopment.
    Keywords:  BRCA1; BRCA2; CIP2A; DDIAS; DNA damage response; PLK1; TOPBP1; brain; cerebral organoids; mitosis; neurodevelopment; rare disease; synthetic lethality; zebrafish
    DOI:  https://doi.org/10.1016/j.cell.2026.07.041
  15. Sci Adv. 2026 Aug 28. 12(35): eaeg8792
    Loss of the mitochondrial SAM transporter reveals a lipoylation-dependent metabolic vulnerability in the postnatal heart.
    Anastasia Rumyantseva, Trevor S Tippetts, Alissa Wilhalm, William Carter, Marco Moedas, Florian A Rosenberger, David Moore, Ákos Végvári, Yvonne Hinze, Linden Muellner-Wong, David Alsina, Rolf Wibom, Rainah Winston, Thomas P Mathews, Lars H Lund, Daniel C Andersson, Gianluigi Pironti, Anna Wedell, Ralph J DeBerardinis, Christoph Freyer, Anna Wredenberg.
      The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S-adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell-cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.
    DOI:  https://doi.org/10.1126/sciadv.aeg8792
  16. J Cell Biol. 2026 Oct 05. pii: e202512059. [Epub ahead of print]225(10):
    Cell cycle-dependent translation-mediated turnover of the long noncoding RNA Malat1.
    Leah M Plasek-Hegde, Yeolhoe Kim, Rahul V Gupta, Emily A Dangelmaier, Sigrid Nachtergaele, Nadya Dimitrova.
      Increased abundance of the nuclear long noncoding RNA (lncRNA) Malat1 drives metastatic progression and is a strong predictor of poor patient prognosis. Although the mechanism that stabilizes Malat1 through processing of its 3' terminus is well-characterized, the pathways governing its turnover remain poorly understood. Here, we show that upon exit from mitosis, Malat1 localizes to the cytoplasm, where it is degraded during early G1, resetting its abundance at the start of each cell cycle. Mechanistically, we demonstrate that Malat1 turnover is mediated by a translation- and Smg1-dependent decay pathway and triggered by redundant elements. Importantly, failure to reset Malat1 levels in early G1, due to decay inhibition or in the absence of progression through mitosis, results in Malat1 accumulation. These findings uncover a cell cycle-dependent mechanism that harnesses the translation machinery to regulate Malat1 abundance and identify cancer cell dormancy as a potential mechanism underlying the widespread overexpression of Malat1 in cancer.
    DOI:  https://doi.org/10.1083/jcb.202512059
  17. Science. 2026 08 27. 393(6814): 895-902
    SGLT2 inhibitors activate pantothenate kinase in the human heart.
    Nicholas Forelli, Trace Thome, Deborah M Eaton, Kollin Schultz, Jiten Patel, Caitlyn E Bowman, Ryo Kawakami, Jae Woo Jung, Ivan A Kuznetsov, Kristina Li, Jialiu A Liang, Kirsten Branch, Claire Brady, Kenneth C Bedi, Yijun Yang, Kaustubh Koya, Nesrine Bouhrira, Emily Megill, Daniel S Kantner, Louis G Smith, Cristin F MacIntosh, Kushol Gupta, Gregory R Bowman, Nathaniel W Snyder, Jonathan Edwards, Kenneth B Margulies, Zoltan Arany.
      Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce mortality in heart failure, but their pharmacological target remains unclear. In this study, we showed that SGLT2i directly activate pantothenate kinase 1 (PANK1), the rate-limiting enzyme in coenzyme A (CoA) synthesis. Using stable isotope infusions, we established that SGLT2i activate CoA synthesis and broadly stimulate fuel use in human cardiac tissue. We also demonstrated that SGLT2i bind PANK1 at physiological concentrations, directly inducing conformational changes and increasing enzymatic activity. In silico modeling identified the site of SGLT2i binding on PANK1, which was confirmed by amino acid mutagenesis. Finally, we showed that SGLT2i-mediated PANK activation is necessary and sufficient to increase contractility of human cardiomyocytes. In summary, we demonstrate off-target activation of PANK1 and promotion of CoA synthesis by SGLT2i, which may explain their marked clinical benefits.
    DOI:  https://doi.org/10.1126/science.aeh4856
  18. Mol Cell. 2026 Aug 24. pii: S1097-2765(26)00520-4. [Epub ahead of print]
    Mitotic single-stranded DNA suppression by DDIAS.
    Yibo Xue, Faisal Bin Rashed, Daniel Y L Mao, Kento T Abe, Zhen-Yuan Lin, Dragomir B Krastev, Dheva Setiaputra, Lisa Hoeg, Clara Bonnet, Arun Kumar, Antranik Mavousian, Arussa Maan, Elizabeth Harvey-Jones, Stephen J Pettitt, Andrew N J Tutt, Christopher J Lord, Frank Sicheri, Anne-Claude Gingras, Daniel Durocher.
      Cells undergoing division mount a unique response to DNA damage that ensures accurate chromosome segregation. The CIP2A-TOPBP1 complex has emerged as an important mitotic genome maintenance factor, but its function remains unclear. Here, we report that DDIAS is a DNA-binding effector of the CIP2A pathway in human cells. DDIAS physically interacts with TOPBP1, and its inactivation causes synthetic lethality with BRCA1 and BRCA2 deficiency. Homologous recombination (HR)-deficient tumors upregulate DDIAS to enable HR-deficient cells to tolerate their genomic instability. Mechanistically, DDIAS is a single-stranded DNA (ssDNA)-binding protein that promotes the repair of ssDNA carried from interphase into mitosis. Mitotic ssDNA in HR-deficient cells is exacerbated by poly(ADP-ribose) polymerase (PARP) inhibition, and DDIAS-dependent suppression of these lesions involves mitotic DNA synthesis, which promotes accurate chromosome segregation and survival. We propose that DDIAS defines a mitotic DNA repair system downstream of CIP2A that mitigates the threat of mitotic ssDNA for genome integrity.
    Keywords:  DNA damage; DNA replication; cancer; genome stability; micronuclei; mitosis; ssDNA; synthetic lethality
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.034
  19. PLoS Biol. 2026 Aug;24(8): e3003954
    Tcf15 promotes an open nucleolar chromatin state to safeguard ribosome biogenesis and genome stability in mouse embryonic stem cells.
    Yu-Ping Dong, Yi-Min Chen, Min Tang, Hu Zhou, Lin Wang, Ping Zheng.
      Embryonic stem cells (ESCs) exhibit a hyperactive chromatin state at ribosomal RNA (rRNA) genes, which not only plays roles in active rRNA synthesis and ribosome biogenesis (RiBi), but also links to genome architecture. However, how this active chromatin state is maintained in ESCs remains poorly understood. Here, we identify Tcf15, a mouse ESC-specific factor, as a novel regulator of ribosomal DNA (rDNA) chromatin state. Tcf15 localizes to the nucleolus, binds the coding region of rRNA genes, and independently recruits epigenetic modifiers-either Tet2 or Rbbp5 (a core component of H3K4 methyltransferases)-to promote an active chromatin configuration. Depletion of Tcf15 increases DNA methylation and H3K27me3 levels at rDNA. Intriguingly, the Tcf15-Rbbp5 axis ensures precursor rRNA transcription and RiBi, whereas the Tcf15-Tet2 axis is not involved in rRNA synthesis. Ribosome profiling further revealed compromised translation of a subset of mRNAs involved in DNA replication, damage response, and repair. Consequently, Tcf15- or Rbbp5-deficient ESCs exhibit severe genomic instability. Our findings add a new regulatory layer of chromatin state in rDNA of stem cells, and reveal a previously unrecognized phenotypic consequence of defective RiBi in ESCs.
    DOI:  https://doi.org/10.1371/journal.pbio.3003954
  20. Nat Genet. 2026 Aug 25.
    Predictive design of tissue-specific mammalian enhancers that function in the mouse embryo.
    Shenzhi Chen, Vincent Loubiere, Ethan W Hollingsworth, Ken Murakami, Nikolaus Mandlburger, Sandra H Jacinto, Atrin Dizehchi, Jacob Schreiber, Evgeny Z Kvon, Alexander Stark.
      Enhancers control tissue-specific gene expression across animals1. Although deep learning2,3 has enabled enhancer prediction and design in mammalian cell lines and non-mammalian model organisms4-10 (reviewed in a previous publication11), it remains unclear whether such approaches can operate within the regulatory complexity of mammalian genomes and tissues in vivo. Here we present a general strategy for designing tissue-specific enhancers that function reliably in mice. We use deep learning to train compact convolutional neural networks on curated chromatin accessibility data and fine-tune them by transfer learning on validated human and mouse enhancers. Guided by these models, we design 15 synthetic enhancers for the heart, limb and central nervous system in mouse embryos, all of which are active in their intended target tissue. These results demonstrate that mammalian enhancer function can be reliably inferred from DNA sequence alone, enabling the predictive de novo design of tissue-specific synthetic enhancers from modest training sets. This work establishes a generalizable framework for programmable control of mammalian gene expression in vivo, opening new avenues in functional genomics, synthetic biology and gene therapy.
    DOI:  https://doi.org/10.1038/s41588-026-02729-1
  21. Immunity. 2026 Aug 26. pii: S1074-7613(26)00321-3. [Epub ahead of print]
    Long-lasting extracellular matrix modifications reshape intestinal stem cell fate and promote chronic inflammation.
    Idan Adir, Carmel Sochen, Sivan Gelb, Aviya Habshush Menachem, Sacha Lebon, Barak Toval, Vladyslav Holiar, Natalia Davidzohn, Tomer-Meir Salame, Irit Rosenhek-Goldian, Simonas Savickas, Fabio Sabino, Valerio Izzi, Bella Ungar, Alon Abend, Inna Solomonov, Ehud Zigmond, Taina Pihlajaniemi, Ulrich Auf dem Keller, Moshe Biton, Irit Sagi.
      Tissue regeneration is viewed as a return to homeostasis, but whether the extracellular matrix (ECM) reverts during recovery from gut inflammation is unclear. Using temporal multi-omics, biomechanical profiling, and spatial fate mapping in colitis models, we showed that colonic ECM underwent lasting pathological reprogramming following inflammation, which we termed modified (mod)ECM. Characterized by collagen XVIII accumulation and immune-driven proteolysis, modECM redirected intestinal stem cells (ISCs) toward a wound-associated epithelial state with a pro-inflammatory transcriptional program. Ex vivo, modECM alone reshaped ISC fate by suppressing Wnt signaling and activating immune recruitment pathways. In vivo, modECM-rich zones sustained T cell infiltration and KRT14+ epithelial cell emergence from Lgr5+ progenitors. This aberrant epithelial program was mirrored in inflamed rectal biopsies from individuals with ulcerative colitis. Our findings redefine the ECM as a long-lived instructive compartment that encodes injury memory and promotes maladaptive regeneration, positioning it as a therapeutic target in chronic inflammatory diseases.
    Keywords:  ECM; ECM remodeling; ISC; T cell recruitment; collagen XVIII; colon; extracellular matrix; intestinal stem cell; pathological reprogramming; tissue regeneration; wound-associated epithelia
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.022
  22. Sci Adv. 2026 Aug 28. 12(35): eaef5385
    Prefoldin function links meiotic chromosome segregation with cellular remodeling and reveals tubulin sensitivity of the meiotic spindle.
    Naohiro Kuwayama, Benjamin S Styler, Bojana Stekovic, Helen Sakharova, Liana Lareau, Marko Jovanovic, Elçin Ünal, Gloria A Brar.
      Faithful chromosome segregation is essential for producing viable gametes during meiosis, a specialized type of cell division relative to mitosis. Here we identify Gim3, a subunit of the ubiquitously expressed and conserved prefoldin complex, as a critical regulator of meiotic but not mitotic chromosome segregation in budding yeast. Loss of Gim3 causes profound defects in chromosome segregation and gamete viability through reduced tubulin protein levels, which are also associated with reduced spindle length. In mitosis, GIM3 deletion minimally affects spindle length and chromosome segregation, despite similarly reduced tubulin levels in both contexts, highlighting an intriguing difference between the sensitivity of meiotic and mitotic spindles to tubulin abundance. Beyond chromosome segregation defects, gim3∆ cells exhibit aberrant meiotic cellular remodeling, including defects in exclusion of age-associated protein aggregates from newly forming gametes. Independently induced meiotic chromosome missegregation similarly disturbs cellular remodeling, pointing to a fundamental coupling between these aspects of gamete production. Together, our findings identify Gim3 as a key factor required for maintaining meiotic chromosome segregation integrity, and reveal an exciting and previously unrecognized link between chromosome segregation and meiotic cellular remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef5385
  23. Science. 2026 Aug 27. 393(6814): eaeh7112
    A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease.
    Jiyi Pang, Aysha H Al-Ani, Komal M Patel, Yunzhuo Zhou, Samuel N Young, Jinjin Chen, Isabella Kong, Marilou Barrios, James A Rickard, Siqi Chen, Xiuquan Ma, Farzaneh Shojaee, Seong-Beom Kim, Siavash Foroughi, Wayne Cawthorne, Annette V Jacobsen, Asha Jois, Ashley L Weir, Lachlan W Whitehead, Pradeep Rajasekhar, Christopher R Horne, Ruqian Lyu, Lucy J Mather, Raymond K H Yip, Ellen Tsui, Imadh Azeez, Tao Tan, Weiwei Liang, Suresh Sivanesan, Andrew Metz, Ash Patwardhan, Natalie Shea, Guru Iyngkaran, Daniel Schneider, Alexander T Elford, William Beattie, Finlay Macrae, Gianmaria Liccardi, Henning Walczak, Yuxia Zhang, Oliver M Sieber, Tim Spelman, Lisa Giulino-Roth, Michael Christie, Yunshun Chen, Kelly L Rogers, Rory Bowden, Sandra E Nicholson, Kate E Lawlor, Edwin D Hawkins, Britt Christensen, Andre L Samson, James E Vince, James M Murphy.
      Inflammatory bowel disease (IBD) is a chronic condition caused by altered cytokine signaling, maladaptive immunity, dysbiosis, and intestinal barrier dysfunction. Although current therapies aim to correct these imbalances to induce remission, most patients ultimately relapse, suggesting that key pathogenic mechanisms persist. Here, we identified aberrant epithelial cell death signaling as an underlying feature of IBD that arises in patients in remission and on advanced therapy. Mechanistically, nascent inflammation skewed epithelial cells into an M1-macrophage-like transcriptional state that promoted RIPK1-independent necroptotic signaling. This signaling then triggered inducible nitric oxide synthase-assisted mitochondrial apoptosis of absorptive epithelial cells and PUMA-mediated intestinal stem cell death. Thus, aberrant epithelial cell death signaling represents a hallmark of IBD that occurs early in mucosal lesion development, persists despite current therapeutic strategies, and predicts clinical relapse.
    DOI:  https://doi.org/10.1126/science.aeh7112
  24. Nat Aging. 2026 Aug 28.
    Mitochondrial DNA leakage in oocytes activates cGAS-STING signaling to drive ovarian aging.
    Min Lei, Zhenye Zhu, Huihui Xie, Chenlu Wei, Jiajia Zhu, Keer Wang, Kexin Zhang, Yongxing Yu, Linli Yang, Xiangyang Zhang, Ning Song, Diyi Xie, Ruizhi Guo, Yanqing Zhao, Aaron J W Hsueh, Yingpu Sun, Qingling Yang.
      Ovarian aging precedes decline in many organs, but its mechanisms remain unclear. Here we show that aging oocytes accumulate cytoplasmic mitochondrial DNA (mtDNA) through increased mtDNA leakage, activating the cyclic GMP-AMP synthase (cGAS) pathway to produce cGAMP and trigger stimulator of interferon genes (STING) signaling. Notably, oocyte-derived cGAMP can pass through gap junctions to surrounding granulosa cells (GCs), activating STING signaling in GCs as well. To model age-associated mitochondrial dysfunction, we generated oocyte-specific Tfam-knockout mice, which recapitulated mtDNA leakage, STING pathway activation in both oocytes and GCs, inflammation and accelerated ovarian dysfunction. We also used Opa1 knockdown and Pink1 deletion oocytes as complementary mitochondrial stress models and observed mtDNA leakage and cGAS-STING activation in both settings. Notably, oocyte-specific Cgas deletion in Tfam mutants or pharmacological STING inhibition with H-151 ameliorated ovarian dysfunction. These findings establish oocyte mtDNA leakage as a causal driver of ovarian aging and nominate cGAS-STING signaling as a therapeutic target.
    DOI:  https://doi.org/10.1038/s43587-026-01195-y
  25. Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00948-4. [Epub ahead of print]45(9): 117870
    Zinc increases stress granule formation by promoting RNA condensation.
    Luisa Macedo de Vasconcelos, Nina Ripin, Roy Parker.
      During cellular stress, mRNAs are condensed into stress granules through the action of G3BP1 and G3BP2. How intracellular conditions affect RNA-protein condensation in stress granules is still unclear. Herein, we present several observations that cells modulate intracellular zinc concentrations to reduce the direct impact of zinc on RNA condensation. We show that oxidative stress increases the intracellular labile zinc and the expression of zinc-sequestering proteins, metallothioneins. Increased intracellular zinc leads to increased stress granule formation and delays stress granule disassembly without increasing translational repression, while zinc depletion decreases stress granule formation, demonstrating that even endogenous levels of free zinc can affect granules. Mechanistically, we demonstrate how zinc promotes stress granule formation by directly stimulating RNA condensation interactions at 100× lower concentrations than magnesium. Together, these data indicate that zinc modulates RNA condensation and stress granule formation and implies an unappreciated potential role for zinc in modulating intracellular RNA structures and interactions.
    Keywords:  CP: cell biology; CP: molecular biology; RNA condensation; oxidative stress; stress granules; zinc
    DOI:  https://doi.org/10.1016/j.celrep.2026.117870
  26. Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00891-0. [Epub ahead of print]45(9): 117813
    The R-loop-SPT6-SETD2 axis safeguards H3K36me3 to prevent broad H3K4me3 invasion in mouse oocytes.
    Yingliang Sheng, Tianyan Guo, Ying Ma, Junzhi Liao, Rong Guo, Kui Ming Chan, Guangjin Pan, Cizhong Jiang, Hongjie Yao.
      The orderly establishment of chromatin modifications is essential for oocyte maturation. However, how R-loops contribute to the crosstalk between histone modifications during oocyte development remains unexplored. Here, we demonstrate that R-loop resolution by RNASEH1 significantly compromises the developmental potential of oocytes. R-loops facilitate H3K36me3 deposition by stabilizing histone H3K36 methyltransferase SETD2 via histone chaperone SPT6 in germinal vesicle (GV) oocytes. Loss of R-loops reduces H3K36me3 levels within oocyte-specific gene bodies, triggering broad H3K4me3 invasion into H3K36me3-marked regions and repression of gene expression. dCas9-mediated site-specific restoration of SETD2 recruitment at R-loop-dependent loci effectively rescues local gene expression. Furthermore, Supt6 overexpression substantially rescues the imbalanced deposition between H3K36me3 and H3K4me3 caused by R-loop loss, corrects dysregulated gene expression, and alleviates the meiotic arrest phenotype. Collectively, our findings establish that R-loops act as critical regulators in balancing H3K36me3 and broad H3K4me3 in the maternal genome, thereby safeguarding proper oocyte development.
    Keywords:  CP: molecular biology; H3K36me3; H3K4me3; Meiotic arrest; Oocyte development; R-loop; SETD2; SPT6
    DOI:  https://doi.org/10.1016/j.celrep.2026.117813
  27. Cell Chem Biol. 2026 Aug 27. pii: S2451-9456(26)00291-6. [Epub ahead of print]
    A STING inhibitor suppresses ferroptosis through radical-trapping antioxidant activity.
    Songlin Yin, Yan Li, Ting Mei, Jiayao Li, Xueting Wang, Xiaoxiao Li, Liguo Yang, Junhong Lin, Weijie Ye, Fujia Lu, Weimin Wang.
      Renal ischemia-reperfusion injury (IRI), a leading cause of acute kidney injury, is driven by coordinated inflammatory signaling and ferroptotic cell death, yet effective therapies remain limited. Here, we show that H-151, a covalent stimulator of interferon genes (STING) inhibitor, also suppresses ferroptosis through a STING-independent mechanism. H-151 functions as a broad-spectrum radical-trapping antioxidant that directly scavenges radicals generated during the Fenton reaction, thereby blocking lipid peroxidation. In a murine renal IRI model, H-151 attenuated tissue damage and restored renal function through concurrent inhibition of STING signaling and ferroptosis. These findings establish radical-trapping antioxidant activity as an additional mechanism of H-151 and identify dual inhibition of inflammatory signaling and ferroptosis as a promising therapeutic strategy for IRI and related disorders.
    Keywords:  H-151; STING; ferroptosis; ischemia reperfusion injury
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.004
  28. Sci Adv. 2026 Aug 28. 12(35): eaeb8946
    Antibody Fc receptor CD16a mediates natural killer cell activation via mechanotransduction of piconewton forces.
    Rong Ma, K Christopher Garcia, Bianxiao Cui, Markus W Covert.
      Natural killer (NK) cells eliminate target cells through antibody-dependent cell-mediated cytotoxicity (ADCC), initiated by CD16a (FcγRIIIa) recognizing the Fc region of antibodies bound to the target cell surface. While the recognition is considered to be driven by CD16a-Fc binding avidity, it fails to explain why Fc multimers inhibit ADCC in solution rather than trigger it. Here, we reveal that CD16a transduces piconewton forces and acts as a mechanosensor to facilitate NK activation. We demonstrate that CD16a force and the actin foci formation associated with it are essential for the phosphorylation of mechanosensitive adaptor Cas-L and signaling adaptor LAT (linker of activation of T cells), reshaping NK cell cytoskeletal dynamics and signaling. Our findings show that NK activation is an intricate process that integrates both biochemical and biophysical information and provide fresh mechanistic insight for immunoengineering.
    DOI:  https://doi.org/10.1126/sciadv.aeb8946
  29. Nat Commun. 2026 Jul 23. pii: 8989. [Epub ahead of print]17(1):
    In situ mapping of late-stage biomechanical coordination during clathrin-mediated endocytosis.
    Bin Wu, Tian Luo, Yu Zhu, Xin Zhang, Dongliang Song, Yanling Lin, Yuanfang Sun, Teng-Xiang Huang, Xiaodong Cheng, Ning Fang.
      Clathrin-mediated endocytosis (CME) requires precise coordination between membrane deformation and force-generating protein assemblies, yet how these forces are dynamically organized in living cells remains poorly defined. Using multi-dimensional single particle tracking (SPT), we indirectly visualize the mechanical motions of individual clathrin-coated pits during the late stages of CME. We uncover a temporally ordered sequence of rotational behaviors that reflect distinct modes of membrane remodeling preceding vesicle scission. While dynamin-dependent in-plane twisting is a common feature of productive CME events, an additional out-of-plane rotational deformation, hereafter referred to as a "swing" motion, is selectively observed at a subset of endocytic sites that recruit actin. This mechanical heterogeneity correlates with differences in membrane deformation and scission efficiency, rather than representing an obligatory step in CME. By capturing these force-generating transitions in situ and under physiological conditions, our work provides a dynamic, biophysical framework for understanding how endocytic protein machines remodel membranes in living cells.
    DOI:  https://doi.org/10.1038/s41467-026-75876-y
  30. Nat Commun. 2026 Jul 22. pii: 8944. [Epub ahead of print]17(1):
    Dysregulated differentiation kinetics underlie the essential role of DNA damage repair in placental development.
    Shanshan Yi, Mingzhu Wang, Qianshu Zhu, Yanxin Huang, Jing Xiao, Ming Zong, Wenju Liu, Xingyi Zhou, Jincan He, Mian Wang, Kexin He, Xiaochen Kou, Yanhong Zhao, Hong Wang, Rui Gao, Shaorong Gao, Guang Yang, Jiayu Chen, Cizhong Jiang.
      The placenta orchestrates maternal-fetal exchanges, and its dysfunction compromises pregnancy outcomes. Somatic cell nuclear transfer (SCNT) placentas offer a model to investigate such dysfunction. However, SCNT placentas exhibit severe pathological features that remain poorly understood. Using single-nucleus multi-omics profiling, we uncover defective differentiation programs in SCNT placentas, including the persistent multipotency of arrested trophoblast precursors and an aberrant differentiation trajectory in the junctional zone. In addition, SCNT placentas demonstrate impaired VEGF signaling, which subsequently compromises labyrinthine vascularization. Mechanistically, we identify reprogramming-induced DNA damage as a core driver of these defects. Furthermore, we trace this genomic instability to the loss of donor cell-inherited H3K27me3 protection, an epigenetic deficiency that correlates with specific DNA damage-associated regions. Consistently, enhancing DNA damage repair pathways restores proper trophoblast differentiation kinetics and vascular transport capacity. Collectively, our study reveals that genomic instability acts as a barrier to placental development, providing a molecular framework to understand compromised placental function.
    DOI:  https://doi.org/10.1038/s41467-026-75623-3
  31. Sci Adv. 2026 Aug 28. 12(35): eaec9028
    Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
    Xiangyi Ding, Sweta Kumari, Ellen F Gregory, Daniel A Starr, G W Gant Luxton.
      Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defective nuclear mechanics and transcriptional regulation, yet these mechanisms cannot explain how lamina defects propagate across the cell to produce the complex pathology of laminopathies. Here, we reveal an emerging pathway linking nuclear lamina dysfunction to cytoplasmic reorganization. Using Caenorhabditis elegans EDMD models, we show that disease-linked lamin variants reduce cytoplasmic mesoscale crowding, increase molecular diffusivity, and disrupt nuclear positioning and endoplasmic reticulum architecture, which mirror phenotypes caused by ribosome depletion. Lamin dysfunction also lowers nucleolar fibrillarin levels and ribosome abundance, revealing a nucleolar-ribosomal axis that transmits nuclear defects to the cytoplasm. Loss of the redundant LEM-domain proteins emr-1 and lem-2 phenocopied lamin mutants, indicating that cytoplasmic disorganization is a shared hallmark of EDMD. These findings connect nuclear architecture to whole-cell biophysics and suggest therapeutic strategies aimed at restoring ribosome function.
    DOI:  https://doi.org/10.1126/sciadv.aec9028
  32. Nat Commun. 2026 08 26. pii: 9057. [Epub ahead of print]17(1):
    State-dependent binding of the wedge domain controls inactivation of the mechanosensitive ion channel PIEZO1.
    Lucas Roettger, Nadja Zeitzschel, Christian Gorzelanny, Clement Verkest, Stefan G Lechner.
      The mechanically activated ion channel PIEZO1 transduces membrane tension into intracellular calcium signals and is critical for a wide range of physiological processes. Recent structural and functional studies have established a detailed framework for PIEZO1 activation, but the molecular mechanisms governing its rapid inactivation remain incompletely understood. Here, we examine the contribution of the intracellular wedge domain to PIEZO1 inactivation using site-directed mutagenesis, electrophysiological recordings and MINFLUX nanoscopy. We show that wedge deletion and disruption of specific π-π and cation-π interactions between the wedge α1-helix and the pore module diminishes inactivation without impairing channel activation. Moreover, MINFLUX nanoscopy suggests that the wedge stabilizes a flat inactivated conformation of PIEZO1 and suggests that wedge dissociation is required for recovery from inactivation. Together, our data support a mechanism with the wedge acting as a state-dependent inactivation particle that docks to the pore module to terminate channel activity during sustained mechanical stimulation.
    DOI:  https://doi.org/10.1038/s41467-026-76927-0
  33. Cell Metab. 2026 Aug 28. pii: S1550-4131(26)00328-1. [Epub ahead of print]
    Host metadherin coordinates hepatic lipid metabolism and CD8+ T cell immunity to promote tumor progression.
    Yong Tang, Ziqing Chen, Hirak Sarkar, Yong Wei, Sereno L Lopez-Darwin, Asael Roichman, Ji Woo Park, Qinglan Li, Cao Fang, Zihong Chen, James Gow, Minhong Shen, Jennifer Shi, Lifei Jiang, Richard Klar, Xiang Hang, Janette R Lugo, Christina J DeCoste, Jennifer M Miller, Wei Wang, Peter Romanienko, Alana L Welm, Ileana M Cristea, Liling Wan, Joshua D Rabinowitz, Yibin Kang.
      Cancer progression is systemically influenced by distant organ dysfunction induced by primary tumors, yet how long-distance tumor-organ crosstalk regulates antitumor immunity remains unclear. Here, we identify host metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout mouse models, we show that concurrent MTDH loss in hepatocytes and CD8+ T cells enhances effector T cell function and suppresses tumor growth and metastasis. Mechanistically, tumor-derived extracellular vesicles and particles (EVPs) activate Kupffer cells to secrete tumor necrosis factor α (TNF-α) and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via nuclear factor κB (NF-κB) signaling. MTDH loss restores hepatic lipid catabolism, reduces systemic lipid levels, and promotes mitochondrial metabolic reprogramming in CD8+ T cells under lipid-reduced conditions, thereby boosting antitumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy. These findings establish host MTDH as a key mediator of tumor-liver crosstalk through metabolic and immune interactions, driving systemic cancer progression.
    Keywords:  CD8(+) T cells; EVP; MTDH; PPARα; extracellular vesicles and particles; immunotherapy; lipid metabolism; tumor-liver interaction
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.003
  34. Elife. 2026 Aug 27. pii: RP111101. [Epub ahead of print]15
    Zasp52's differentially expressed intrinsically disordered region confers thin filament stability at the Z-disc.
    Nikolai Ho, Frieder Schöck.
      The Drosophila scaffolding protein Zasp52 is required to maintain structure at the muscle Z-disc, which experiences strong forces during contraction. It is alternatively spliced into many isoforms, some of which contain a long intrinsically disordered region (IDR). We show that this region is primarily expressed in the indirect flight muscle (IFM) and is required for maintaining the integrity of the Z-disc. Deleting the IDR-encoding exon 15e results in flightlessness and structural IFM defects, including sarcomere bending at the Z-disc and an inability to de-contract. These defects are indicative of a lack of proper thin filament anchoring to the Z-disc. This is further supported by a genetic interaction between exon 15e and actin. Fluorescence recovery after photobleaching of an isoform lacking exon 15e shows that the IDR is required for maintaining Zasp52 at the Z-disc and thereby stabilizing Z-discs. Lastly, we can rescue these phenotypes by restricting IFM use. Together, these results suggest that Zasp52's IDR confers thin filament stability at the Z-disc of IFM.
    Keywords:  Alp/Enigma family protein; D. melanogaster; LDB3; cell biology; indirect flight muscle; intrinsically disordered region; myofibril; sarcomere
    DOI:  https://doi.org/10.7554/eLife.111101
  35. Nat Rev Mol Cell Biol. 2026 Aug 27.
    Towards a systems-level view of the microtubule cytoskeleton and its functions in physiology and disease.
    Carsten Janke, Anna Akhmanova, Francesca Bartolini, Satish Bodakuntla, Filippo Del Bene, Virginie Hamel, Timothy J Mitchison, Thomas Müller-Reichert, François Nédélec, Eva Nogales, Gaia Pigino, Antonina Roll-Mecak, Giampietro Schiavo, Thomas Surrey, Zdenek Lansky.
      Microtubules are well-researched components of the cytoskeleton, yet we lack a holistic understanding that bridges molecular and cellular details with the broader functions of the microtubule cytoskeleton in development, ageing and disease. For example, how microtubule properties and functions are affected by tubulin post-translational modifications, disease-related mutations or variation of the microtubule lattice remains unexplored. In this Roadmap, we argue that integrating various experimental and theoretical approaches to bridge different spatial and temporal scales will offer new opportunities for gaining insights into essential cellular mechanisms and physiology, eventually revealing how microtubule dysfunction can lead to a broad spectrum of human diseases. Built on the current state of the art in the microtubule field, our Roadmap highlights future opportunities and challenges and proposes ways to tackle them. Given the many fundamental questions remaining to be answered, the microtubule cytoskeleton will continue to inspire scientists as it has been doing for decades.
    DOI:  https://doi.org/10.1038/s41580-026-01011-w
  36. Mol Cell. 2026 Aug 28. pii: S1097-2765(26)00557-5. [Epub ahead of print]
    HoT auto-blinking probes enable real-time, super-resolution chromatin imaging in live cells and tissues.
    Aiping Wang, Shanshan Liu, Heng Shi, Mikhail Rotkevich, Carlotta Viana, Hui Zhong, Limei Zhong, Lingkuan Meng, Yanwu Li, Guirong Chen, Xiaoming Zhu, Zhenzhen Ma, Bing Fu, Alvaro Castells-Garcia, Jie Zhang, Hongyan Sun, Maria Pia Cosma.
      Single-molecule localization microscopy (SMLM) enables visualization of chromatin architecture at nanoscale resolution. However, high-performance DNA probes suitable for SMLM in both live cells and tissues remain limited. We developed Hoechst-6-Carboxytetramethylrhodamine (6-TAMRA) derivative (HoT) probes-rhodamine-based derivatives conjugated to a Hoechst moiety-through structural fine-tuning of rhodamine spirocyclization. HoTs are self-assembling, auto-blinking probes with excellent photostability and high temporal resolution. They permeate live cells, enabling long-term, real-time nanoscopic chromatin imaging in live and fixed cells and in tissue sections. In live cells, we identified nanoscale features in the 3D organization of chromatin and quantified DNA fiber kinetics at high resolution. We quantified DNA compaction in single cells within retinal and colon cancer sections. OligoSTORM (stochastic optical reconstruction microscopy)-labeled gene loci can be visualized and measured within their HoT-labeled chromatin footprints. Our work provides powerful tools for investigating chromatin structure and functions in living cells and tissues, with applications ranging from cancer diagnosis to retinal regeneration.
    Keywords:  3D chromatin organization; DNA-binding fluorescent probes; Hoechst–rhodamine probes; SMLM; auto-blinking fluorophores; chromatin compaction; chromatin nanostructure; live-cell super-resolution imaging; oligoSTORM; single-molecule ocalization microscopy; tissue super-resolution microscopy
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.010
  37. Sci Adv. 2026 Aug 28. 12(35): eaeg1148
    Insulin-like growth factor-binding protein 7 is a soluble cell adhesion molecule.
    Kai Cai, Xuewu Zhang, Xiao-Chen Bai.
      Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein with diverse roles in angiogenesis, cell differentiation, tissue remodeling, and regulating cell signaling and is linked to numerous human diseases. The molecular basis of the multifunctionality of IGFBP7 remains unclear. Using cryo-electron microscopy, we show that IGFBP7 assembles into a barrel-shaped dodecamer in the presence of heparin. The carboxyl-terminal IgC2 domain forms the central core of the barrel, which is capped by the amino-terminal heparin-binding IB domain at both ends. This homo-oligomer can simultaneously engage heparan sulfate proteoglycans on adjacent cells, functioning as a soluble "cell glue" to drive cell-cell adhesion. Furthermore, IGFBP7 enhances and prolongs signaling of receptor tyrosine kinases, including insulin receptor and c-MET, through its adhesion activity. These findings reveal a structural mechanism for IGFBP7's pleiotropy and establish it as a universal adhesion factor.
    DOI:  https://doi.org/10.1126/sciadv.aeg1148
  38. Nat Commun. 2026 Jul 30. pii: 9224. [Epub ahead of print]17(1):
    Condensation of MATCAP promotes CENP-E-dependent chromosome congression in mitosis.
    Tongtong Yang, Wenping Hu, Panpan Xu, Huanyu Li, Yaqian Zhang, Fangyuan Xiong, Yunze Li, Chao Xu, Ke Ruan, Zhonghuai Hou, Zhikai Wang, Liangyu Zhang, Xuebiao Yao, Shengqi Xiang, Kai Jiang, Xing Liu.
      Accurate segregation of mitotic chromosomes requires pre-anaphase alignment driven by microtubule-based motor proteins. Tubulin detyrosination is essential to guide CENP-E-driven chromosome congression in mitosis. However, the mechanisms of action and physiochemical properties of the detyrosinases for decoding CENP-E motility remain elusive. Here we show that microtubule-associated tyrosine carboxypeptidase (MATCAP) undergoes intrinsically disordered region (IDR)-dependent liquid-liquid phase separation (LLPS) on microtubules to constitute the tubulin detyrosination machinery. These biomolecular condensates selectively enrich tubulin and CENP-E, thereby stabilizing kinetochore-microtubule attachments. Real-time imaging of cells expressing LLPS-deficient MATCAP mutants reveals the importance of MATCAP LLPS dynamics in mitotic chromosome alignment. Mechanistically, phase separation of MATCAP spatiotemporally couples tubulin detyrosination with CENP-E motility to ensure a robust chromosome alignment during mitosis. These findings delineate a signaling cascade that integrates phase separation and tubulin detyrosination with mitotic progression for the maintenance of genomic stability.
    DOI:  https://doi.org/10.1038/s41467-026-75440-8
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