bims-ginsta Biomed News
on Genome instability
Issue of 2025–08–24
fourteen papers selected by
Jinrong Hu, National University of Singapore



  1. Cell. 2025 Aug 12. pii: S0092-8674(25)00814-1. [Epub ahead of print]
      Nuclear pore complexes (NPCs) bridge across the nuclear envelope and mediate nucleocytoplasmic exchange. They consist of hundreds of nucleoporin building blocks and exemplify the structural complexity of macromolecular assemblies. To ensure transport directionality, different nucleoporin complexes are attached to the cytoplasmic and nuclear face of the NPC. How those asymmetric structures are faithfully assembled onto the symmetric scaffold architecture that exposes the same interaction surfaces to either side remained enigmatic. Here, we combine cryo-electron tomography, subtomogram averaging, and template matching with live imaging to address this question in budding yeast and Drosophila. We genetically induce ectopic nuclear pores and show that pores outside the nuclear envelope are symmetric. We furthermore demonstrate that the peripheral NPC configuration is affected by the nucleotide state of the small GTPase Ran. Our findings indicate that the nuclear transport system is self-regulatory, namely that the same molecular mechanism controls both transport and transport channel composition.
    Keywords:  Ran GTPase; asymmetry; biogenesis; cryo-ET; heterogeneity; in situ structural biology; nuclear envelope; nuclear pore complex; nucleoporins
    DOI:  https://doi.org/10.1016/j.cell.2025.07.025
  2. Cell. 2025 Aug 14. pii: S0092-8674(25)00857-8. [Epub ahead of print]
      Hair loss affects millions globally, significantly impacting quality of life and psychological well-being. Despite its prevalence, effective strategies for promoting human hair growth remain elusive. By investigating congenital generalized hypertrichosis terminalis (CGHT), a rare genetic disorder characterized by excessive hair growth, we discover that chromatin deletions or an inverted duplication disrupt the topologically associating domain (TAD), leading to the upregulation of the potassium channel KCNJ2 in dermal fibroblasts. Mouse genetics demonstrate that KCNJ2-mediated membrane hyperpolarization in dermal fibroblasts promotes hair growth by enhancing fibroblasts Wnt signaling responses, involving a reduction in intracellular calcium levels. Notably, fibroblast membrane potential oscillates during the normal hair cycle, with hyperpolarization specifically associated with the growth phase. Inducing fibroblast membrane depolarization delays the growth phase, while KCNJ2-mediated hyperpolarization rescues hair loss in aging and androgenetic alopecia models. These results uncover a previously unrecognized role of fibroblast bioelectricity in tissue regeneration, offering novel therapeutic avenues for hair loss treatment.
    Keywords:  KCNJ2; bioelectric signaling; fibroblast niche; hair follicle regeneration
    DOI:  https://doi.org/10.1016/j.cell.2025.07.035
  3. Nat Commun. 2025 Aug 18. 16(1): 7670
      Transposable elements (TEs) are genomic elements present in multiple copies in mammalian genomes. TEs were thought to have little functional relevance but recent studies report roles in biological processes, including embryonic development. To investigate the expression dynamics of TEs during human early development, we generated long-read sequence data from human pluripotent stem cells (hPSCs) in vitro differentiated to endoderm, mesoderm, and ectoderm lineages to construct lineage-specific transcriptome assemblies and accurately place TE sequences. Our analysis reveals that specific TE superfamilies exhibit distinct expression patterns. Notably, we observed TE switching, where the same family of TE is expressed in multiple cell types, but originates from different transcripts. Interestingly, TE-containing transcripts exhibit distinct levels of transcript stability and subcellular localization. Moreover, TE-containing transcripts increasingly associate with chromatin in germ layer cells compared to hPSCs. This study suggests that TEs contribute to human embryonic development through dynamic chromatin interactions.
    DOI:  https://doi.org/10.1038/s41467-025-63080-3
  4. Proc Natl Acad Sci U S A. 2024 Aug 13. 121(33): e2402291121
      The mammalian mitochondrial genome (mtDNA) is multicopy and its copy number (mtCN) varies widely across tissues, in development and in disease. Here, we systematically catalog this variation by assaying mtCN in 52 human tissues across 952 donors (10,499 samples from the Genotype-Tissue Expression project) and 20 murine tissues using qPCR, capturing 50- and 200-fold variation, respectively. We also estimate per cell mtCN across 173 human cell lines from the Cancer Cell Line Encyclopedia using whole-genome sequencing data and observe >50-fold variation. We then leverage the vast amount of genomics data available for these repositories to credential our resource and uncover mtDNA-related biology. Using already existing proteomics data, we show that variation in mtCN can be predicted by variation in TFAM, histone, and mitochondrial ribosome protein abundance. We also integrate mtCN estimates with the CRISPR gene dependency measurements to find that cell lines with high mtCN are resistant to loss of GPX4, a glutathione phospholipid hydroperoxidase. Our resource captures variation in mtCN across mammalian tissues and should be broadly useful to the research community.
    Keywords:  GPX4; TFAM; histone; mitochondrial ribosome; mtDNA
    DOI:  https://doi.org/10.1073/pnas.2402291121
  5. EMBO J. 2025 Aug 18.
      Loss of pluripotency is an essential step in post-implantation development that facilitates the emergence of somatic cell identities essential for gastrulation. Before implantation, pluripotent cell identity is governed by a gene regulatory network that includes the key transcription factors SOX2 and NANOG. However, it is unclear how the pluripotency gene regulatory network is dissolved to enable lineage restriction. Here, we show that SOX2 is required for post-implantation pluripotent identity in the mouse, and cells that lose SOX2 expression in the posterior epiblast are no longer pluripotent. Using in vitro and in vivo analyses, we demonstrate anticorrelated expression of NANOG and SOX2 preceding gastrulation, culminating in an early disappearance of pluripotent identity from posterior NANOGhigh/SOX2low epiblast. Surprisingly, Sox2 expression is repressed by NANOG and embryos with post-implantation deletion of Nanog maintain posterior SOX2 expression. Our results demonstrate that the distinctive features of post-implantation pluripotency are underpinned by altered functionality of pluripotency transcription factors, ensuring correct spatio-temporal loss of embryonic pluripotency.
    Keywords:  Embryo; NANOG; Pluripotency; Post Implantation; SOX2
    DOI:  https://doi.org/10.1038/s44318-025-00527-9
  6. Annu Rev Cell Dev Biol. 2025 Aug 19.
      Bioelectricity is likely as old as life itself. From the moment the first proto-cell was enclosed in a lipid bilayer, a membrane potential arose. Thus, one can expect that bioelectrical activities influence single-cell and collective cell behaviors in processes such as embryo development, tissue repair, and even disease. Despite the ubiquity of bioelectrical phenomena, most research has focused on bioelectrical control of neural tissues, and as a result, our knowledge of nonneural contexts remains comparatively less understood, scattered, and often misunderstood. Still, there are strong reasons for supporting the idea that bioelectricity contributes to diverse morphogenetic contexts. Thus, in this review we provide an overview of the current knowledge of how cells generate and perceive bioelectrical inputs, and discuss how cells translate these stimuli into responses that influence tissue morphogenesis in physiology and pathology.
    DOI:  https://doi.org/10.1146/annurev-cellbio-101323-032747
  7. Biophys J. 2025 Aug 18. pii: S0006-3495(25)00524-7. [Epub ahead of print]
      The mechanical properties of the cytoplasm and nucleoplasm are crucial for the correct and robust functioning of a cell and play a key role in understanding how mechanical signals are transferred to the nucleus. Here, we demonstrate remarkable shape mimicry between the cellular and nuclear shape of oocytes, following the externally applied deformation without direct contact between the cell cortex and the nucleus. This effect arises from a surprisingly soft and fluid-like nucleoplasm that barely resists external strain, while the viscoelastic cytoplasm drives shape transmission. Comparative studies in jellyfish, starfish, and mouse oocytes reveal that lower cytoplasmic elasticity in jellyfish leads to reduced nuclear shape mimicry, highlighting the role of cytoplasmic mechanics in nuclear deformation.
    DOI:  https://doi.org/10.1016/j.bpj.2025.08.012
  8. Nat Commun. 2025 Aug 18. 16(1): 7665
      During development, epithelia function as malleable sheets that undergo extensive remodeling to shape developing embryos. Optogenetic control of Rho signaling provides an avenue to investigate mechanisms of epithelial morphogenesis, but transgenic optogenetic tools can be limited by variability in expression levels and deleterious effects of transgenic overexpression on development. Here, we use CRISPR/Cas9 to tag Drosophila RhoGEF2 and Cysts/Dp114RhoGEF with components of the iLID/SspB optogenetic heterodimer, permitting light-dependent control over endogenous protein activities. Using quantitative optogenetic perturbations, we uncover a dose-dependence of tissue furrow depth and bending behavior on RhoGEF recruitment, revealing mechanisms by which developing embryos can shape tissues into particular morphologies. We show that at the onset of gastrulation, furrows formed by cell lateral contraction are oriented and size-constrained by basal actomyosin. Our findings demonstrate the use of quantitative, 3D-patterned perturbations of cell contractility to precisely shape tissue structures and interrogate developmental mechanics.
    DOI:  https://doi.org/10.1038/s41467-025-62483-6
  9. Nat Commun. 2025 Aug 18. 16(1): 7662
      Vertebrate inner ear mechanosensory hair cells detect sound and gravitational forces. Additionally, fishes have homologous lateral line hair cells in the skin that detect water vibrations for orientation and predator avoidance. Hair cells in the lateral line and ear of fishes and other non-mammalian vertebrates regenerate readily after damage, but mammalians lack this ability, causing deafness and vestibular defects. As yet, experimental attempts at hair cell regeneration in mice result in incompletely differentiated and immature hair cells. Despite differences in regeneration capabilities, the gene regulatory networks (GRNs) driving hair cell maturation during development are highly similar across vertebrates. Here, we show that the transcription factor prdm1a plays a key role in the hair cell fate GRN in the zebrafish lateral line. Mutating prdm1a respecifies lateral line hair cells into ear hair cells, altering morphology and transcriptome. Understanding how transcription factors control diverse hair cell fates in zebrafish is crucial for understanding the yet unsolved regeneration of diverse hair cells in mammalian ears to restore hearing and balance.
    DOI:  https://doi.org/10.1038/s41467-025-62942-0
  10. Nat Cardiovasc Res. 2025 Aug 19.
      Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia.
    DOI:  https://doi.org/10.1038/s44161-025-00687-1
  11. Nat Cell Biol. 2025 Aug 18.
      From single-cell extrusion to centimetre-sized wounds, epithelial gaps of various sizes and geometries appear across organisms. Their closure involves two orthogonal modes: lamellipodial crawling at convex edges and purse string-like movements at concave edges. The mechanisms driving this curvature-dependent migration remain unclear. Here we perform an intracellular cartography to reveal that in both micropatterned and naturally arising gaps, the endoplasmic reticulum (ER) undergoes edge curvature-dependent morphological reorganizations, forming tubules at convex edges and sheets at concave edges. This reorganization depends on cytoskeleton-generated protrusive and contractile forces. Mathematical modelling reveals that these morphologies minimize strain energy under their respective geometric regime. Functionally, ER tubules at the convex edge favour perpendicularly oriented focal adhesions, supporting lamellipodial crawling, while ER sheets at the concave edge favour parallelly oriented focal adhesions, supporting purse string-like movements. Altogether, ER emerges as a central mechanotransducer, integrating signals from cytoskeletal networks to orchestrate two orthogonal modes of cell migration.
    DOI:  https://doi.org/10.1038/s41556-025-01729-3
  12. Elife. 2025 Aug 18. pii: RP107114. [Epub ahead of print]14
      Homologous recombination (HR) preserves genomic stability by repairing double-strand DNA breaks and ensuring efficient DNA replication. Central to HR is the strand-exchange reaction taking place within the three-stranded synapsis wherein a RAD51 nucleoprotein filament binds to a donor DNA. Here, we present the cryoEM structure of a displacement loop of human RAD51 that captures the synaptic state when the filament has become tightly bound to the donor DNA. The structure elucidates the mechanism of strand exchange by RAD51, including the filament engagement with the donor DNA, the strand invasion and pairing with the complementary sequence of the donor DNA, the capture of the non-complementary strand and the polarity of the strand-exchange reaction. Our findings provide fundamental mechanistic insights into the biochemical reaction of eukaryotic HR.
    Keywords:  D-loop; DNA repair; RAD51; chromosomes; cryoEM; gene expression; homologous recombination; human; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.107114
  13. Cell. 2025 Aug 14. pii: S0092-8674(25)00856-6. [Epub ahead of print]
      RNA Pol II-mediated transcription is essential for eukaryotic life. Although loss of transcription is thought to be universally lethal, the associated mechanisms promoting cell death are not yet known. Here, we show that death following the loss of RNA Pol II activity does not result from dysregulated gene expression. Instead, it occurs in response to loss of the hypophosphorylated form of Rbp1 (also called RNA Pol IIA). Loss of RNA Pol IIA exclusively activates apoptosis, and expression of a transcriptionally inactive version of Rpb1 rescues cell viability. Using functional genomics, we identify the mechanisms driving lethality following the loss of RNA Pol IIA, which we call the Pol II degradation-dependent apoptotic response (PDAR). Using the genetic dependencies of PDAR, we identify clinically used drugs that owe their lethality to a PDAR-dependent mechanism. Our findings unveil an apoptotic signaling response that contributes to the efficacy of a wide array of anti-cancer therapies.
    Keywords:  BCL2L12; DNA damage; PTBP1; RNA polymerase II; apoptosis; cancer therapy; cell death; chemotherapy; cisplatin; transcription
    DOI:  https://doi.org/10.1016/j.cell.2025.07.034
  14. Nat Commun. 2025 Aug 19. 16(1): 7724
      Biomolecular phase separation is an emerging theme for protein assembly and cellular organisation. The collective forces driving such condensation, however, remain challenging to characterise. Here we show that tracking the dilute phase concentration of only one component suffices to quantify composition and energetics of multicomponent condensates. Applying this assay to several disease- and stress-related proteins, we find that monovalent ions can either deplete from or enrich within the dense phase in a context-dependent manner. By analysing the effect of the widely used modulator 1,6-hexanediol, we find that the compound inhibits phase separation by acting as a solvation agent that expands polypeptide chains. Extending the strategy to in cellulo data, we even quantify the relative energetic contributions of individual proteins within complex condensates. Together, our approach provides a generic and broadly applicable tool for dissecting the forces governing biomolecular condensation and guiding the rational modulation of condensate behaviour.
    DOI:  https://doi.org/10.1038/s41467-025-62437-y