bims-ginsta Biomed News
on Genome instability
Issue of 2026–01–04
27 papers selected by
Jinrong Hu, National University of Singapore
  1. Atypical E-cadherin attachments mediate melanoblast migration through confined epithelial spaces.
  2. Self-Organizing Ovarian Somatic Organoids Preserve Cellular Heterogeneity and Reveal Cellular Contributions to Ovarian Aging.
  3. Live Imaging of Mouse Embryonic Stem Cells and Embryos: Protocols for In Vitro Culture, Microscopy, and Image Data Analysis.
  4. Actomyosin-dependent assembly of the mechanosensitive machinery from adherens junctions triggers actin polymerization and organization.
  5. Centrosome clustering in cancer cells requires microtubule assembly through a RanGTP-dependent TPX2-KIFC1 interaction.
  6. Longevity of cardiac and skeletal muscle proteins is dependent on tissue and subcellular compartmentation patterns.
  7. Mechanical forces regulate the composition and fate of stalled nascent chains.
  8. Drosophila Abi maintains blood cell homeostasis by promoting clathrin-mediated endocytosis of Notch.
  9. A competition model of multilineage priming and cell-fate decisions.
  10. DEAF1 - a transcriptional brake on muscle autophagy.
  11. p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism.
  12. Organization of replicated chromosomes by DNA loops and sister chromatid cohesion.
  13. Senescent cells secrete chromatin components via senescence-associated extracellular particles.
  14. Real-Time Super-Resolution Tracking of mtDNA Remodeling and Inflammatory Release with a Selective Fluorescent Probe.
  15. Trade-off between branching and polarity controls decision-making during cell migration.
  16. A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects.
  17. Single-strand deaminase-assisted editing for functional RNA manipulation.
  18. The membrane transition strongly enhances biopolymer condensation through prewetting.
  19. Shear stress governs hematopoietic stem cell fate to promote inflammation-induced aging.
  20. Long noncoding RNA regulation of immunity.
  21. Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy.
  22. A breakage-replication/fusion process explains complex rearrangements and segmental DNA amplification.
  23. Single-cell lineage tracing identifies hemogenic endothelial cells in the adult mouse bone marrow.
  24. Circumferential actomyosin bundles anchored by CCM1 drive endothelial cell contraction and vessel constriction.
  25. p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.
  26. Self-renewal of neuronal mitochondria through asymmetric division.
  27. Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease.
  1. J Cell Biol. 2026 Mar 02. pii: e202508144. [Epub ahead of print]225(3):
    Atypical E-cadherin attachments mediate melanoblast migration through confined epithelial spaces.
    Denay J K Richards, Brandon M Trejo, Parijat Sil, Abhishek Biswas, Rebecca A Jones, Lionel Larue, Danelle Devenport.
      Epithelial tissues are populated with accessory cells including pigment-producing melanocytes, which must migrate between tightly adherent epithelial cells, but how cells migrate through confined epithelial spaces without impairing barrier function is poorly understood. Using live imaging of the mouse epidermis, we captured the migration of embryonic melanocytes (melanoblasts) while simultaneously visualizing the basement membrane or epithelial surfaces. We show that melanoblasts migrate through basal and suprabasal layers of the epidermis where they use keratinocyte surfaces, as well as the basement membrane, as substrates for migration. Melanoblasts form atypical and dynamic E-cadherin attachments to keratinocytes that largely lack cytoplasmic catenins known to anchor E-cadherin to F-actin. We show E-cadherin is needed in both melanoblasts and keratinocytes to stabilize migratory protrusions, and that depleting E-cadherin results in reduced melanoblast motility and ventral depigmentation in adult mice. These findings illustrate how migratory cells modify the cell adhesion machinery to invade between connected epithelial cells without interrupting the skin barrier.
    DOI:  https://doi.org/10.1083/jcb.202508144
  2. Aging Cell. 2026 Jan;25(1): e70333
    Self-Organizing Ovarian Somatic Organoids Preserve Cellular Heterogeneity and Reveal Cellular Contributions to Ovarian Aging.
    Shweta S Dipali, Aubrey Converse, Madison Q Gowett, Pratik Kamat, Emily J Zaniker, Abigail Fennell, Teresa Chou, Michele T Pritchard, Mary Zelinski, Jude M Phillip, Francesca E Duncan.
      Ovarian somatic cells are essential for reproductive function, but no existing ex vivo models recapitulate the cellular heterogeneity or interactions within this compartment. We engineered an ovarian somatic organoid model by culturing a stroma-enriched fraction of mouse ovaries in scaffold-free agarose micromolds. Self-organized ovarian somatic organoids maintained diverse cell populations, produced extracellular matrix, and secreted hormones. Organoids generated from reproductively old mice exhibited reduced aggregation and growth compared to young counterparts, as well as differences in cellular composition. Interestingly, matrix fibroblasts from old mice demonstrated upregulation of pathways associated with the actin cytoskeleton and downregulation of cell adhesion pathways, indicative of increased cellular stiffness that may impair organoid aggregation. Cellular morphology, which is regulated by the cytoskeleton, significantly changed with age and in response to actin modulation. Moreover, actin modulation altered organoid aggregation efficiency. Overall, ovarian somatic organoids have advanced knowledge of cellular contributions to ovarian aging.
    Keywords:  actin; cellular stiffness; organoid; ovary; reproductive aging; stroma
    DOI:  https://doi.org/10.1111/acel.70333
  3. Methods Mol Biol. 2025 Dec 30.
    Live Imaging of Mouse Embryonic Stem Cells and Embryos: Protocols for In Vitro Culture, Microscopy, and Image Data Analysis.
    Woonyung Hur, Mohamed I Gatie, Alexandre Francou, Anna-Katerina Hadjantonakis.
      Live imaging is a cornerstone technique in developmental and stem cell biology, enabling visualization of dynamic features in cells, tissues, and embryos. Here, we present current protocols for live imaging of mouse pluripotent stem cells (mESCs) and pre- and postimplantation embryos using confocal and light-sheet microscopy. These methods integrate optimized ex utero culture conditions, mounting geometries, and environmental control systems to support long-term, physiologically relevant imaging with minimal phototoxicity. We outline approaches for imaging pluripotent stem cells under distinct culture states, as well as strategies for embryo imaging compatible with normal growth and morphogenesis. Finally, we discuss computational workflows for image processing, segmentation, and cell tracking that enable quantitative analysis of lineage dynamics. Together, these protocols provide a comprehensive and reproducible framework for investigating cell state transitions and morphogenetic processes in mammalian development.
    Keywords:  Cell tracking; Embryo culture; Embryonic stem cells; Image analysis; Laser point scanning confocal microscopy; Light-sheet confocal microscopy; Live imaging; Mouse; Pluripotency; Postimplantation embryo; Preimplantation embryo; Segmentation; Stem cell culture
    DOI:  https://doi.org/10.1007/7651_2025_690
  4. Sci Adv. 2026 Jan 02. 12(1): eady4863
    Actomyosin-dependent assembly of the mechanosensitive machinery from adherens junctions triggers actin polymerization and organization.
    Aurélie Favarin, Rayan Said, Hong Wang, Emilie Zeine, Amaury Pierrard, Julien Pernier, Hemalatha Narassimprakash, Stéphane Roméro, Alexis M Gautreau, René-Marc Mège, Christophe Le Clainche.
      Cells rely on cadherin-based adherens junctions (AJs) to form cohesive tissues. To establish contact, cells generate pushing forces through branched actin polymerization mediated by the actin-related protein 2/3 (Arp2/3) complex, followed by the reinforcement of mechanosensitive AJs in response to actomyosin contractility. To investigate how AJ proteins coordinate these events, we combined kinetic assays of actin polymerization, single actin filament observation in total internal reflection fluorescence microscopy, and in vitro reconstitution of AJ mechanosensitivity. Our findings show that actomyosin contractility alone is sufficient to trigger the hierarchical assembly of the AJ mechanosensitive proteins α-catenin, vinculin, and vasodilator-stimulated phosphoprotein (VASP). Once assembled, these proteins act synergistically to promote actin filament nucleation, elongation, and bundling. The α-catenin-vinculin-VASP machinery inhibits Arp2/3-mediated actin branching and instead promotes the myosin-dependent assembly of actin bundles. Together, these results reveal how AJs integrate actin assembly, actomyosin contractility, and mechanosensitivity in a feedback loop.
    DOI:  https://doi.org/10.1126/sciadv.ady4863
  5. Curr Biol. 2025 Dec 30. pii: S0960-9822(25)01616-1. [Epub ahead of print]
    Centrosome clustering in cancer cells requires microtubule assembly through a RanGTP-dependent TPX2-KIFC1 interaction.
    Georgina Garrido, Jacopo Scrofani, Ana Arsenijevic, Alvaro Aranguren, Francisco Martínez-Jiménez, Eva Borràs, Eduard Sabidó, Isabelle Vernos.
      Aneuploidy, chromosomal instability (CIN), and centrosome amplification are hallmarks of aggressive solid tumors. Cancer cells with supernumerary centrosomes ensure bipolar spindle formation by efficiently clustering them at the spindle poles. TPX2 (targeting protein for Xenopus kinesin-like protein 2), a nuclear and microtubule-associated protein, and its partner, the Aurora-A kinase (AURKA), are key mitotic players frequently co-overexpressed in human cancers. TPX2 overexpression ranks first in the CIN70 signature, and both TPX2 and AURKA are part of the CIN4 chromosomal instability signature, with prognostic value in breast cancer patients. Using proximity biotinylation assays (BioID), we identified the mitotic interactome of TPX2 and AURKA. Ten of their high-confidence proximity interactors are highly correlated with TPX2 and AURKA in cancer. We further validate the interaction of TPX2 and AURKA with one of them, KIFC1, a minus-end-directed kinesin-like motor that has a role in centrosome clustering in cancer cells. We show that TPX2 and KIFC1 cooperate to ensure robust acentrosomal microtubule nucleation and organization. Our data show that this mechanism plays a major role in the clustering of supernumerary centrosomes in cancer cells.
    Keywords:  Aurora-A; BioID; KIFC1; RanGTP; TPX2; cancer; centrosome clustering; microtubules; mitosis; spindle
    DOI:  https://doi.org/10.1016/j.cub.2025.11.075
  6. Cell Rep. 2025 Dec 30. pii: S2211-1247(25)01540-2. [Epub ahead of print]45(1): 116768
    Longevity of cardiac and skeletal muscle proteins is dependent on tissue and subcellular compartmentation patterns.
    Jack Gugel, Jordan Currie, Lorena Alamillo, Jason Flint, Keun-Young Kim, Marc Debliqui, Mark H Ellisman, Maggie P Y Lam, Edward Lau, Rafael Arrojo E Drigo, Leslie Leinwand.
      Myocytes are exceptionally long-lived cells that must maintain proteome integrity over decades while adjusting for changes in functional output and metabolic demand. We used in vivo stable isotope labeling combined with mass spectrometry proteomics and correlated multi-isotope imaging mass spectrometry to quantify and visualize protein turnover across cardiac, fast-twitch, and slow-twitch skeletal muscles, creating a resource of hundreds of individual protein turnover rates from each tissue. We found that cardiac muscle has the highest rate of protein turnover, followed by slow-twitch skeletal muscle and then fast-twitch skeletal muscle, and that these different rates of protein turnover are driven by different levels of muscle use, rather than myosin isoform composition. We also identified protein age heterogeneity at the myofiber and sarcomere levels. These findings uncover fundamental principles of muscle protein maintenance and have broad implications for understanding cellular aging, muscle disease, and the design of therapeutic strategies targeting muscle protein turnover.
    Keywords:  CP: Metabolism; CP: Molecular biology; actin; cardiac muscle; half-life; long-lived proteins; multi-isotope imaging; protein turnover; skeletal muscle; stable-isotope labeling
    DOI:  https://doi.org/10.1016/j.celrep.2025.116768
  7. Mol Cell. 2025 Dec 30. pii: S1097-2765(25)00982-7. [Epub ahead of print]
    Mechanical forces regulate the composition and fate of stalled nascent chains.
    Danish Khan, Ananya A Vinayak, Cole S Sitron, Onn Brandman.
      The ribosome-associated quality control (RQC) pathway resolves stalled ribosomes. As part of RQC, stalled nascent polypeptide chains (NCs) are appended with CArboxy-Terminal amino acid tails (CAT tails) in an mRNA-free, non-canonical elongation process. The relationship between CAT tail composition (alanine [Ala] and threonine [Thr] in yeast) and function has remained unknown. Using biochemical approaches in yeast, we discovered that mechanical forces on the NC regulate CAT tailing. We propose that CAT tailing initially operates in "extrusion mode," which increases NC lysine accessibility for on-ribosome ubiquitylation. Thr in CAT tails prevents the formation of polyalanine, which forms α-helices that lower extrusion efficiency and disrupt termination of CAT tailing. After NC ubiquitylation, pulling forces on the NC switch CAT tailing to an Ala-only "release mode," which facilitates NC release and degradation. Failure to switch from extrusion to release mode leads to the accumulation of NCs on large ribosomal subunits and proteotoxic aggregation of Thr-rich CAT tails.
    Keywords:  CAT tails; RQC; mechanochemistry; protein folding; protein quality control; ribosome; ribosome stalling; ribosome-associated quality control; translation
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.008
  8. J Cell Biol. 2026 Mar 02. pii: e202505091. [Epub ahead of print]225(3):
    Drosophila Abi maintains blood cell homeostasis by promoting clathrin-mediated endocytosis of Notch.
    Hyun Gwan Park, Seunghwan Song, Joohyung Kim, Seungbok Lee.
      Abl-interactor (Abi) proteins induce actin polymerization by activating Wiskott-Aldrich syndrome protein (WASp) or SCAR/WASP-family verprolin-homologous protein. Loss of mammalian Abi1 causes myeloproliferative neoplasm; however, little is known about how the Abi family of actin-regulatory proteins regulates blood cell homeostasis. Here, we demonstrate that Drosophila Abi promotes plasmatocyte-to-crystal cell transdifferentiation but represses plasmatocyte-to-lamellocyte transdifferentiation through Notch signaling. Consistent with a previously demonstrated role of clathrin-mediated endocytosis (CME) in Notch signaling activation, we find that Abi promotes Notch-CME by recruiting WASp and the Notch receptor to nascent sites of CME. Finally, we demonstrate that CME and crystal cell formation are inhibited by Abelson (Abl)-mediated phosphorylation of Abi but require PTP61F, a phosphatase that reverses this phosphorylation. Our findings identify Abi as a critical integrator of actin remodeling and Notch-CME and reveal opposing roles of Abl and PTP61F in regulating Abi activity to maintain blood cell homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202505091
  9. Cell Rep. 2025 Dec 31. pii: S2211-1247(25)01462-7. [Epub ahead of print]45(1): 116690
    A competition model of multilineage priming and cell-fate decisions.
    Tobias Steinschaden, Louis Faure, Ruslan Soldatov, Igor Adameyko.
      The transition from a single cell to a body of trillions requires each cell to make fate decisions, committing to one identity among many possible options. This review aims to examine how progenitors and stem cells generate diverse fates through multilineage priming and the competitive interplay of biasing gene-expression programs. Microheterogeneity among progenitors, combined with differential fate biases, gives rise to cell populations with collective multipotency, an emergent state in which the population self-regulates to balance the production of all downstream fates during embryogenesis. We discuss how progenitor cells navigate the epigenetic landscape to control descendant cell-type proportions and how multilineage priming helps reconcile inductive, communication-driven modes of development with autonomous, self-intrinsic fate selection. In parallel, we review computational approaches that leverage single-cell transcriptomics, clonal lineage tracing, and multiomics integration to reconstruct developmental trajectories, identify biases, and dissect the mechanisms of fate selection and commitment.
    Keywords:  CP: Developmental biology; CP: Stem cell research
    DOI:  https://doi.org/10.1016/j.celrep.2025.116690
  10. Autophagy. 2025 Dec 31. 1-2
    DEAF1 - a transcriptional brake on muscle autophagy.
    Wen Xing Lee, Kah Yong Goh, Sze Mun Choy, Hong-Wen Tang.
      Macroautophagy/autophagy protects muscle from proteotoxic stress and maintains tissue homeostasis, yet skeletal muscle relies on it more than most organs. Adult fibers endure constant mechanical strain and require continuous turnover of long-lived proteins, while muscle stem cells (MuSCs) depend on autophagy to remain quiescent, activate after injury, and regenerate effectively. How autophagy is transcriptionally regulated in muscle has been unclear. We identified DEAF1 as a transcriptional brake on autophagy. In MuSCs, DEAF1 controls activation and regeneration and becomes aberrantly elevated with age, promoting protein aggregate formation and cell death. In muscle fibers, DEAF1 is chronically induced during aging, suppressing autophagy and driving functional decline. Exercise reverses DEAF1 induction, restoring autophagy and muscle function. These findings reveal DEAF1 as a key regulator linking autophagy to regeneration and aging, highlighting a therapeutically tractable axis for preserving muscle health.
    Keywords:  Autophagy; DEAF1; muscle; muscle stem cell; regeneration
    DOI:  https://doi.org/10.1080/15548627.2025.2610451
  11. Nat Genet. 2025 Dec 29.
    p53 inactivation drives breast cancer metastasis to the brain through SCD1 upregulation and increased fatty acid metabolism.
    Kathrin Laue, Sabina Pozzi, Johanna Zerbib, Rebecca Bertolio, Yonatan Eliezer, Yael Cohen-Sharir, Tom Winkler, Manuel Caputo, Alessia A Ricci, Lital Adler, Rami Khoury, Giuseppe Longobardi, Rachel Slutsky, Alicia I Leikin-Frenkel, Shai Ovadia, Katharina Lange, Alessandra Rustighi, Silvano Piazza, Andrea Sacconi, Rayna Y Magesh, Faith N Keller, Jean Berthelet, Alexander Schäffer, Ron Saad, Sahar Israeli Dangoor, Karolina Szczepanowska, Iris Barshack, Yang Liao, Sergey Malitsky, Alexander Brandis, Thomas Broggini, Marcus Czabanka, Wei Shi, Delphine Merino, Emma V Watson, Giovanni Blandino, Ayelet Erez, Ruth Ashery-Padan, Hind Medyouf, Luca Bertero, Giannino Del Sal, Ronit Satchi-Fainaro, Uri Ben-David.
      Brain metastasis (BM) carries a poor prognosis, yet the molecular basis of brain tropism remains unclear. Analysis of breast cancer BM (BCBM) revealed pervasive p53 inactivation through mutations and/or aneuploidy, with pathway disruption already present in primary tumors. Functionally, p53 inactivation markedly increased BCBM formation and growth in vivo, causally linking p53 perturbation to BM. Mechanistically, p53 inactivation upregulated SCD1 and fatty acid synthesis (FAS), essential for brain-metastasizing cells; SCD1 knockout abolished the p53-dependent growth advantage. Molecularly, p53 suppressed SCD1 directly through promoter binding and indirectly by downregulating its co-activator DEPDC1. Astrocytes further enhanced FAS by secreting factors that were metabolized in a p53-dependent manner, promoting tumor survival, proliferation and migration. Finally, p53-deficient tumors were sensitive to FAS inhibition ex vivo and in vivo. Thus, we identify p53 inactivation as a driver of BCBM, reveal p53-dependent and astrocyte-dependent FAS modulation and highlight FAS as a therapeutically targetable BCBM vulnerability.
    DOI:  https://doi.org/10.1038/s41588-025-02446-1
  12. Nat Rev Mol Cell Biol. 2026 Jan 02.
    Organization of replicated chromosomes by DNA loops and sister chromatid cohesion.
    Fena Ochs, Daniel W Gerlich.
      Cohesin is a key regulator of three-dimensional genome organization, contributing to gene regulation, recombination, DNA repair and chromosome segregation. Like other members of the evolutionary conserved structural maintenance of chromosomes (SMC) protein-complex family, cohesin folds DNA through motor-driven loop extrusion. Cohesin has a unique, second activity of genome organization: it physically links sister chromatids together in replicated chromosomes, a process termed sister chromatid cohesion. Sister chromatid cohesion and loop extrusion are mediated by two distinct pools of cohesin, which share common core subunits, but associate with distinct regulatory subunits to interact with chromosomes in fundamentally different ways. In this Review, we discuss how sister chromatid cohesion is established and regulated, and how an interplay between cohesion and chromatin loops organizes replicated chromosomes. We also discuss how cohesion supports chromosome segregation in mitosis and meiosis, and how it contributes to DNA double-strand break repair and age-related oocyte aneuploidy. We outline recent technological advances that provide new opportunities to study cohesion and the conformation of replicated chromosomes, and we provide a perspective on how these tools might be applied to answer fundamental questions in cohesin biology.
    DOI:  https://doi.org/10.1038/s41580-025-00933-1
  13. bioRxiv. 2025 Dec 16. pii: 2025.12.12.694055. [Epub ahead of print]
    Senescent cells secrete chromatin components via senescence-associated extracellular particles.
    Sviatlana Zaretski, Jose L Nieto Torres, Xue Lei, John P Nolan, Malene Hansen, Peter D Adams.
      Senescent cells influence their surroundings through the senescence-associated secretory phenotype (SASP), an assortment of secreted molecules and macromolecular complexes. Among SASP's intracellular drivers are cytoplasmic chromatin fragments (CCFs), nuclear-derived DNA that activates the pro-inflammatory cGAS/STING pathway. While autophagy contributes to CCFs degradation, the full repertoire of CCF fates and signaling functions remains unclear. Here, we show that senescent cells release CCF components, ɣH2AX and double-stranded DNA (dsDNA), into the extracellular space via an ESCRT-independent multivesicular body pathway. Secreted CCF components localize to extracellular particles exhibiting an unusual "popcorn"-like morphology, distinct from canonical small extracellular vesicles. Notably, inhibition of autophagy enhances secretion of CCF components and particles, suggesting an inverse relationship between intracellular clearance and extracellular release. A fraction of CCF-containing extracellular particles activates cGAS-STING signaling in non-senescent proliferating cells and is enriched in the circulation of aged mice, pointing to a previously unrecognized mode of extracellular signaling by senescent cells.
    DOI:  https://doi.org/10.64898/2025.12.12.694055
  14. Angew Chem Int Ed Engl. 2025 Dec 30. e20934
    Real-Time Super-Resolution Tracking of mtDNA Remodeling and Inflammatory Release with a Selective Fluorescent Probe.
    Shixian Cao, Caixia Sun, Xin-Yue Zhang, Changyu Yoon, Zhiqiang Liu, Jiyoung Yoo, Yujin Kim, Xiaoqiang Yu, Yunjie Xu, Jong Seung Kim, Kang-Nan Wang.
      Mitochondrial DNA (mtDNA) is vital for mitochondrial function and cellular homeostasis, with its spatiotemporal dynamics are tightly linked to development, metabolism, and disease progression. However, super-resolution tracking of mtDNA in live cells remains limited by lack of selective, photostable small-molecule probes. Here, we present mtNARed, a rationally engineered, wash-free fluorescent probe featuring a large Stokes-shift, and high photostability that enables super-resolution tracking of mtDNA dynamics in live cells using stimulated emission depletion (STED) microscopy, with complementary readouts by fluorescence-lifetime imaging microscopy (FLIM). mtNARed precisely localizes to mitochondrial nucleoids and supports long-term imaging while minimizing interference from nuclear DNA. This capability generalizes across diverse mammalian cell types, including highly polarized sperm cells. Importantly, under mitochondrial stress or inflammatory stimulation, mtNARed reports in situ and at super-resolution of the progressive release of mtDNA, correlating with mitochondrial depolarization, membrane disintegration, and immune activation. This work provides a robust and versatile platform for advanced mtDNA imaging, opening opportunities to dissect mitochondrial genome dynamics, maintenance, and signaling across physiological and pathological states.
    Keywords:  STED super resolution imaging; mtDNA dynamics tracking; mtDNA remodeling & inflammatory release; mtDNA selective targeting probe
    DOI:  https://doi.org/10.1002/anie.202520934
  15. Sci Adv. 2026 Jan 02. 12(1): eads2734
    Trade-off between branching and polarity controls decision-making during cell migration.
    Jiayi Liu, Javier Boix-Campos, Jonathan E Ron, Johan M Kux, Magdalena E M Oremek, Adriano G Rossi, Nir S Gov, Pablo J Sáez.
      Motile cells often face microenvironmental constraints and obstacles that force them to extend multiple protrusions. However, the analysis of shape dynamics during directional decision-making has been restricted to single junctions. Here, we combined live-cell imaging and a coarse-grained model to study the migratory behavior of highly branched cells while simultaneously facing several junctions. The theoretical model predicts that the choice of a new direction is determined by the competition between the cellular protrusions in the form of seesaw oscillations. We found that macrophages and endothelial cells display different regimes moving on hexagonal networks, despite sharing a mesenchymal (i.e., adhesion-dependent) migratory strategy. The model describes the motility of both cell types and reveals a trade-off between branching and speed: Having many protrusions allows local microenvironmental exploration for directional cues, but long-range migration efficiency improves with fewer protrusions. Collectively, our data highlight the relevance and provide insights for the regulation of shape dynamics during cell navigation in complex geometries.
    DOI:  https://doi.org/10.1126/sciadv.ads2734
  16. Nat Cardiovasc Res. 2025 Dec 29.
    A disrupted compartment boundary underlies abnormal cardiac patterning and congenital heart defects.
    Irfan S Kathiriya, Martin H Dominguez, Kavitha S Rao, Jonathon M Muncie-Vasic, W Patrick Devine, Kevin M Hu, Swetansu K Hota, Bayardo I Garay, Diego Quintero, Piyush Goyal, Megan N Matthews, Reuben Thomas, Tatyana Sukonnik, Dario Miguel-Perez, Sarah Winchester, Emily F Brower, André Forjaz, Pei-Hsun Wu, Denis Wirtz, Ashley L Kiemen, Benoit G Bruneau.
      Failure of septation of the interventricular septum (IVS) is the most common congenital heart defect, but mechanisms for patterning the IVS are largely unknown. Here we show that a Tbx5+/Mef2cAHF+ progenitor lineage forms a compartment boundary bisecting the IVS. This coordinated population originates at a first and second heart field interface. Ablation of Tbx5+/Mef2cAHF+ progenitors causes IVS disorganization, right ventricular hypoplasia and mixing of IVS lineages. Reduced dosage of the congenital heart defect transcription factor TBX5 disrupts boundary position and integrity, resulting in ventricular septation defects and patterning defects, including misexpression of Slit2 and Ntn1, which encode guidance cues. Reducing NTN1 dosage partly rescues cardiac defects in Tbx5 mutant embryos. Loss of Slit2 or Ntn1 causes ventricular septation defects and perturbed septal lineage distributions. Thus, we identify Tbx5 as a candidate selector gene, directing progenitors and regulating essential cues, to pattern a compartment boundary for proper cardiac septation, revealing mechanisms for cardiac birth defects.
    DOI:  https://doi.org/10.1038/s44161-025-00755-6
  17. Nat Biotechnol. 2026 Jan 02.
    Single-strand deaminase-assisted editing for functional RNA manipulation.
    Yuan Zhuang, Qingguo Zhu, Hao Wu, Xiangyue Lin, Yongchang Yan, Puze Geng, Rong Yang, Ruoyu Shen, Yuhao Zhang, Zhixin Lei, Haowei Meng, Aidan Wang, Mingyao Cui, Huifen Xiang, Chengqi Yi.
      Rewriting RNA information to alter function requires controllable tools to edit RNA sequences within a user-defined region. Here we report a single-strand deaminase-assisted platform for adjustable RNA information manipulation (AIM). AIM is composed of a loop-forming guide RNA bound to an RNA-targeting Cas protein and an evolved TadA. AIM induces a loop, flanked by paired regions, in the target RNA; the loop size can be adjusted to allow conversions of single and multiple bases. We evolve TadA to achieve A-to-I, C-to-U or simultaneous A+C editing in coding and noncoding regions. We apply AIM to suppress the ochre nonsense codon (UAA) in disease-relevant cell and animal models, in which the two As must be simultaneously edited to rewrite the coding information. Moreover, we use AIM to manipulate adjacent phosphorylation sites important for protein function. Collectively, AIM is a versatile platform for manipulating RNA information within user-defined regions, opening additional avenues for functional RNA modulation.
    DOI:  https://doi.org/10.1038/s41587-025-02956-7
  18. Nat Chem Biol. 2026 Jan 02.
    The membrane transition strongly enhances biopolymer condensation through prewetting.
    Yousef Bagheri, Mason N Rouches, Benjamin B Machta, Sarah L Veatch.
      Biopolymers that separate into condensed and dilute phases in solution also prewet membranes when one or more components couple to membrane lipids. Here we demonstrate that this prewetting transition becomes exquisitely sensitive to lipid composition when membranes have compositions near the boundary of liquid-ordered/liquid-disordered phase coexistence in both simulation and in reconstitution when polyelectrolytes are coupled to model membranes. In cells, we use an optogenetic tool to characterize prewetting at both the plasma membrane (PM) and the endoplasmic reticulum (ER) and find that prewetting is potentiated or inhibited by perturbations of membrane composition. Prewetting can also mediate membrane adhesion, with avidity dependent on membrane composition, as demonstrated in cells through the potentiation or inhibition of ER-PM contact sites. The strong correspondence of results in simulation, reconstitution and cells reveals a new role for membrane lipids in regulating the recruitment and assembly of soluble proteins.
    DOI:  https://doi.org/10.1038/s41589-025-02082-0
  19. Nat Aging. 2026 Jan 02.
    Shear stress governs hematopoietic stem cell fate to promote inflammation-induced aging.
    Tongyao Shang, Li Zhao, Shibo Ying, Lida Su, Yue Yang, Jiadong Liu, Yingying Wang, Jipeng Xue, Cheng Cheng, Yixin Wu, Shiyao Chen, Hongmei Dong, Xuequn Chen, Hailin Ma, Qi Zhang, Tingbo Liang, Wei Yang, Ye Feng, Marong Fang, Xinjiang Lu.
      Hematopoietic stem cells (HSCs) reside in the bone marrow in a quiescent state, but can be mobilized into the blood in response to inflammation, cytokine stimulation, nervous activity or hypoxia. Chronic inflammation, a hallmark of aging, accelerates HSC aging by promoting myeloid-biased differentiation and reducing self-renewal capacity, yet the role of mechanical stimulation in regulating these processes remains poorly understood. Here, we found that PIEZO1 senses shear stress in blood flow to induce HSC proliferation and myelopoiesis. We show that shear stress induces PIEZO1-mediated ion currents and Ca2+ influx in both mouse and human HSCs, with downstream effects on proliferation and myeloid differentiation mediated via JAM3 and CAPN2 pathways. GsMTx4, a PIEZO1 antagonist, attenuated inflammation-induced aging in mice by inhibiting HSC activation. These findings link the mechanical sensor PIEZO1 to HSC proliferation and myeloid differentiation via multi-tiered signaling, highlighting its role in accelerating inflammation-induced aging.
    DOI:  https://doi.org/10.1038/s43587-025-01039-1
  20. Nat Immunol. 2026 Jan 02.
    Long noncoding RNA regulation of immunity.
    Bingfei Yu, Howard Y Chang.
      Genes encoding long noncoding RNAs (lncRNAs) are intimately involved in mammalian immunity. Here we review recent knowledge of how lncRNAs regulate immune cell specification and function. Beyond canonical roles in nuclear architecture, chromatin modification and posttranscriptional regulation, lncRNA regulation of metabolic pathways, antigenic extracellular lncRNA ribonucleoprotein complexes and glycosylated noncoding RNAs on the cell surface have emerged as newly recognized regulatory mechanisms. In the immune system, specific lncRNAs control lineage determination during hematopoiesis as well as immune cell activation and function during immune responses, while lncRNA dysregulation is associated with immune-related diseases. In particular, we highlight how a female-specific lncRNA XIST promotes female-biased autoimmunity. Finally, we discuss emerging technologies in high-throughput functional genomics, human genetics, molecular interaction mapping, artificial intelligence and synthetic biology that are accelerating our understanding of lncRNA biology in immunity and beyond.
    DOI:  https://doi.org/10.1038/s41590-025-02355-9
  21. J Am Chem Soc. 2026 Jan 02.
    Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy.
    Tian Qiu, Yeuan Ting Lee, Brendan G Dwyer, Yi Jer Tan, Ting Chen, Bryan A Romero, Yanlan Wang, Jiehui Deng, Tinghu Zhang, Gerald R Crabtree, Stephen M Hinshaw, Kwok-Kin Wong, Nathanael S Gray.
      Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response (DDR) to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair, particularly in homologous recombination-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce "DNA damage chemical inducers of proximity" (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemically induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1, which induces the DDR and apoptosis in cancer cells at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis in vitro, leading to antitumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well-tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical-induced proximity as a strategy for modulating the DDR in cancer.
    DOI:  https://doi.org/10.1021/jacs.5c17396
  22. Nat Genet. 2026 Jan 02.
    A breakage-replication/fusion process explains complex rearrangements and segmental DNA amplification.
    Cheng-Zhong Zhang, Carlos Mendez-Dorantes, Kathleen H Burns, David Pellman.
      Segmental copy-number gains are major contributors to human genetic variation and disease, but how these alterations arise remains incompletely understood. Here, based on the analyses of both experimental evolution and human disease genomes, we describe a general mechanism of segmental copy-number gain from a rearrangement process termed 'breakage-replication/fusion'. The hallmark genomic feature of breakage-replication/fusion is adjacent parallel breakpoints: two or more rearrangement breakpoints derived from replication of a single ancestral DNA end. We show that adjacent parallel breakpoints are a widespread feature of DNA duplications in human disease genomes and experimental models of chromothripsis. In addition to adjacent parallel breakpoints, breakage-replication/fusion also explains two other patterns of complex rearrangements with unclear provenance: chains of short (≤1 kb) insertions and high-level amplification consisting of inverted segments. Together, these findings revise the mechanistic model for chromothripsis and provide a new conceptual framework for understanding the origin of segmental DNA duplication during genome evolution.
    DOI:  https://doi.org/10.1038/s41588-025-02434-5
  23. bioRxiv. 2025 Oct 10. pii: 2025.10.09.681472. [Epub ahead of print]
    Single-cell lineage tracing identifies hemogenic endothelial cells in the adult mouse bone marrow.
    Jing-Xin Feng, Mei-Ting Yang, Lili Li, Caiyi C Li, Ferenc Livák, Jack Chen, Yongmei Zhao, Dunrui Wang, Avinash Bhandoola, Naomi Taylor, Giovanna Tosato.
      During mouse development, hematopoietic stem and progenitor cells (HSPC) originate from hemogenic endothelial cells (ECs) through a process of endothelial-to-hematopoietic transition. These HSPC are thought to fully sustain adult hematopoiesis. However, it remains unknown whether adult ECs retain hemogenic potential. Here we used in vivo genetic lineage tracking at population and single-cell (sc) levels, scRNA sequencing, and bone marrow transplantation to detect hemogenic ECs in adult mice. We identify and characterize a small population of bone marrow-resident, adult Cdh5 /VE-Cadherin + ECs that produce hematopoietic cell-progeny in vitro and in mice. These adult hemogenic ECs and their hematopoietic cell progeny can give rise to hematopoietic cells following adoptive transfer into adult mice. Furthermore, blood cells generated from adult and developmental ECs comparably home to peripheral tissues, where they similarly contribute to inflammatory responses. Thus, our results identify previously unrecognized bone marrow-derived adult hemogenic ECs that generate HSPC and functional mature blood cells.
    DOI:  https://doi.org/10.1101/2025.10.09.681472
  24. Nat Commun. 2025 Dec 27.
    Circumferential actomyosin bundles anchored by CCM1 drive endothelial cell contraction and vessel constriction.
    Yan Chen, Nuria Taberner, Jason da Silva, Vivek Semwal, Biplab Bhattacherjee, Julia Eckert, Igor Kondrychyn, Mingzhao Hu, Nitish Aswani, Guihua Chen, Yasushi Okada, Anne Karine Lagendijk, Tatsuo Shibata, Satoru Okuda, Li-Kun Phng.
      Blood vessels undergo extensive remodelling to acquire appropriate diameters, yet how endothelial cells coordinate changes in their number and shape to achieve this remains unclear. Here we show that endothelial cell contraction and rearrangements underlie the inverse relationship between cell number and vessel diameter during development. Using high-resolution imaging and manipulation of actin cytoskeleton organisation, in vivo laser ablation experiments and mathematical simulations, we reveal that tension-bearing, circumferential actomyosin bundles form in the endothelial cortex to drive endothelial cell contraction and vessel constriction. The anchorage of circumferential actin bundles to cell-cell junctions is mediated by Ccm1/Krit1 protein. Importantly, the loss of circumferential actin bundles in ccm1-deficient endothelial cells causes cell enlargement and impaired vessel constriction, culminating in vessel dilation characteristic of cerebral cavernous malformations. Our multiscale study demonstrates how circumferential actomyosin-driven endothelial cell contractions regulate vessel diameter and provides insights into mechanisms of both normal vascular development and disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-67820-3
  25. J Cell Biol. 2026 Mar 02. pii: e202503087. [Epub ahead of print]225(3):
    p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.
    Jordan Matthew Ngo, Justin Krish Williams, Morayma Mercedes Temoche-Diaz, Abinayaa Murugupandiyan, Randy Schekman.
      Exosomes are multivesicular body-derived extracellular vesicles that are secreted by metazoan cells. Exosomes have utility as disease biomarkers, and exosome-mediated miRNA secretion has been proposed to facilitate tumor growth and metastasis. Previously, we demonstrated that the Lupus La protein (La) mediates the selective incorporation of miR-122 into metastatic breast cancer-derived exosomes; however, the mechanism by which La itself is sorted into exosomes remains unknown. Using unbiased proximity labeling proteomics, biochemical fractionation, superresolution microscopy, and genetic tools, we establish that the selective autophagy receptor p62 sorts La and miR-122 into exosomes. We then performed small RNA sequencing and found that p62 depletion reduces the exosomal secretion of tumor suppressor miRNAs and results in their accumulation within cells. Our data indicate that p62 is a quality control factor that modulates the miRNA composition of exosomes. Cancer cells may exploit p62-dependent exosome cargo sorting to eliminate tumor suppressor miRNAs and thus to promote cell proliferation.
    DOI:  https://doi.org/10.1083/jcb.202503087
  26. bioRxiv. 2025 Dec 18. pii: 2025.12.17.694973. [Epub ahead of print]
    Self-renewal of neuronal mitochondria through asymmetric division.
    Tejashree Pradip Waingankar, Camryn Zurita, Angelica E Lang, Cliff Vuong, Ahmad Shami, Diana Bautista, Catherine Drerup, Samantha C Lewis.
      Mitochondrial ATP production is essential for life. Mitochondrial function depends on the spatio-temporal coordination of nuclear and mitochondrial genome expression, yet how this coordination occurs in highly polarized cells such as neurons remains poorly understood. Using high-resolution imaging in mouse peripheral sensory neurons and zebrafish larvae, we identified a sub-population of mitochondria enriched in mtDNA that are positioned at the collateral branch points of long sensory neurites, both in vitro and in vivo . While the mitochondria in neurites are generally depleted of mtDNA, those at axon branch points preferentially engage in mtDNA replication and transcription, accumulate nuclear-encoded mitochondrial mRNA, and are spatially linked to nascent cytosolic peptide synthesis. The mtDNA-positive mitochondrial pool exhibits asymmetric genome partitioning at division, shedding highly motile daughters that lack mtDNA. Asymmetric division rejuvenates the membrane potential of the mtDNA-rich, biogenesis-dedicated mitochondria. We also found that, in peripheral sensory neurons, axonal mitochondria rarely fuse or share matrix contents, explaining how differentiated daughters maintain their distinct composition and fate after fission. Thus, division-coupled mitochondrial self-renewal is yoked to neurite topology in sensory neurons, patterning mitochondrial diversity and homeostasis from micron to meter scales.
    DOI:  https://doi.org/10.64898/2025.12.17.694973
  27. Neuron. 2025 Dec 30. pii: S0896-6273(25)00890-6. [Epub ahead of print]
    Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease.
    Sandeep Kumar Dubey, Divya Chaubey, Chiseko Ikenaga, Wen-Wen Lin, Hugo J Bellen, Thomas E Lloyd.
      Defective nucleocytoplasmic transport (NCT) has emerged as a contributing factor in the pathogenesis of neurodegenerative diseases and aging. Valosin-containing protein (VCP) is an AAA+ATPase required for disassembly of protein complexes, and mutations in VCP cause neurodegenerative and neuromuscular diseases. We find that VCP is required for quality control of nuclear pore complexes (NPCs) by extracting selected nucleoporins from NPCs for proteasome-mediated degradation. Pathogenic VCP variants cause a reduction in nucleoporins in Drosophila, induced pluripotent stem cell (iPSC)-derived motor neurons, and muscle biopsies from patients, indicating a dominant gain-of-function mechanism. Mechanistically, disease-associated mutations in VCP result in increased recruitment to NPCs through interactions with Ufd1-Npl4, leading to the removal of a subset of nucleoporins from NPCs and disrupting NCT. These findings show that the VCP-Ufd1-Npl4 pathway regulates NPC quality control and that disease-associated variants aberrantly activate the VCP-Ufd1-Npl4 complex to degrade NPCs and disrupt NCT.
    Keywords:  ALS; Drosophila; TDP-43; VCP; muscle disease; neurodegeneration; nuclear pore complex; nucleocytoplasmic transport; nucleoporin; protein quality control
    DOI:  https://doi.org/10.1016/j.neuron.2025.11.017
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