bims-ginsta Biomed News
on Genome instability
Issue of 2026–08–09
25 papers selected by
Jinrong Hu, National University of Singapore
  1. Mitotic MAX bookmarking drives MYC-dependent hypertranscription at TBP-bound promoters.
  2. Cell size reduction distinctly scales spindle elongation and chromosome segregation in C. elegans.
  3. An ancient mitochondrial program tunes translation to haem availability.
  4. The mechanosensitive protein Zyxin influences Hippo signaling and tissue growth via adherens junctions and basal spot junctions in Drosophila.
  5. ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
  6. Damage recognition by intestinal stem cells via Draper promotes adult Drosophila midgut regeneration.
  7. Coordination of ALT telomere maintenance across the cell cycle.
  8. An expanded codebook of human transcription factor DNA-binding specificity.
  9. DCAF11-dependent molecular glue degrader activated by glutathionylation.
  10. Volume EM reveals desmosome three-dimensional architecture in epithelial cells and tissue models.
  11. A primitive endoderm-centric view of mammalian development.
  12. Structure and function of the centromere and inner kinetochore.
  13. A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
  14. High-resolution mapping of embryonic genome activation unveils a decoupling of transcription activation from precocious H3K4me3 removal.
  15. α-Satellite RNA maintains centromeric cohesion through R-loops.
  16. CDK5RAP3-Mediated Mitochondrial RQC Alleviates Pathological Cardiac Hypertrophy.
  17. Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
  18. STAT5A-α-actinin axis links actin integrity to mitochondrial homeostasis and innate immune activation.
  19. BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin.
  20. A metabolic view of gastrulation: Coordinating signalling, epigenetics and morphogenesis.
  21. The mitochondria enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation.
  22. LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development.
  23. Why studying females reveals more about aging: The reproductive resilience hypothesis for the evolution of sex-specific aging.
  24. Vimentin bridges scales to convert polarized cell locomotion into coordinated collective migration.
  25. Reducing the mechanical load reawakens adult cardiomyocyte proliferation.
  1. Genes Dev. 2026 Aug 06.
    Mitotic MAX bookmarking drives MYC-dependent hypertranscription at TBP-bound promoters.
    Inma Gonzalez, Lieng Taing, Almira Chervova, Pedro Escoll, Luis Altamirano-Pacheco, Alina Sommer, Teresa Urli, Maxim V C Greenberg, Véronique Legros, Guillaume Chevreux, Florian Mueller, Agnès Dubois, Pablo Navarro.
      Faithful genome reactivation after mitosis is essential for cell identity, yet the mechanisms driving global postmitotic transcription remain unclear. Here, we show that the MYC oncogene and its obligate partner MAX drive a postmitotic hypertranscriptional state in mouse embryonic stem cells. Cell cycle-resolved single-cell RNA-seq in inducible Max -/- cells reveals that early G1 hypertranscription is strongly impaired without MAX. Mechanistically, MAX remains bound to thousands of promoters during mitosis, while MYC is largely excluded. Using high-temporal-resolution profiling, pharmacological inhibition of MYC/MAX, and acute MAX degradation at mitotic exit, we demonstrate that MAX mitotic binding triggers rapid MYC recruitment and transcriptional amplification of TBP-bound promoters by enhancing RNA polymerase II occupancy and efficient initiation and elongation. These findings redefine MYC/MAX as master regulators of gene regulatory inheritance across mitosis.
    Keywords:  Myc/Max; hypertranscription; mitotic bookmarking
    DOI:  https://doi.org/10.1101/gad.354072.126
  2. Nat Commun. 2026 Aug 06. pii: 7929. [Epub ahead of print]17(1):
    Cell size reduction distinctly scales spindle elongation and chromosome segregation in C. elegans.
    Chukwuebuka William Okafornta, Reza Farhadifar, Gunar Fabig, Hai-Yin Wu, Maria Köckert, Martin Vogel, Daniel Baum, Robert Haase, Michael J Shelley, Daniel J Needleman, Thomas Müller-Reichert.
      How embryos adapt their internal cellular machinery to reductions in cell size during development remains a fundamental question in cell biology. Here, we use high-resolution lattice light-sheet fluorescence microscopy and automated image analysis to quantify lineage-resolved mitotic spindle and chromosome segregation dynamics from the 2- to 64-cell stages in Caenorhabditis elegans embryos. While spindle length scales with cell size across both wild-type and size-perturbed embryos, chromosome segregation dynamics remain largely invariant, suggesting that distinct mechanisms govern these mitotic processes. Combining femtosecond laser ablation with large-scale electron tomography, we find that mid-spindle microtubules mediate chromosome segregation dynamics and remain uncoupled from cell size across all stages of early development. In contrast, spindle elongation is driven by cortically anchored motor proteins and astral microtubules, rendering it sensitive to cell size. Incorporating these experimental results into an extended stoichiometric model for both the spindle and chromosomes, we find that allowing only cell size and microtubule catastrophe rates to vary reproduces spindle pole-to-pole dynamics across development. The same model also accounts for centrosome separation and pronuclear positioning in the one-cell C. elegans embryo, spindle-length scaling across nematode species spanning ~100 million years of divergence, and spindle rotation in human cells. Thus, a unified stoichiometric framework provides a predictive, mechanistic account of spindle and nuclear dynamics across scales and species.
    DOI:  https://doi.org/10.1038/s41467-026-76360-3
  3. Nature. 2026 Aug 05.
    An ancient mitochondrial program tunes translation to haem availability.
    Xiang Zhang, Max-Hinderk Schuler, Gonca Çetin, Eva-Maria Eckl, Lara Rheinemann, Julia Mergner, Barbara Steigenberger, Andreas Pichlmair, Lucas T Jae.
      Anaemia is a major global health burden that affects one-quarter of the human population and annually accounts for over 50 million years of healthy life lost1. It arises from nutritional iron deficiency, hereditary disorders (including thalassaemia and sickle cell disease) and malaria, and is characterized by haemoglobin imbalances2. Haem-the active component of haemoglobin-is both essential and potentially toxic, which necessitates tight control of levels. However, the molecular circuitry that monitors haem levels remains obscure. The cytosolic eIF2α kinase HRI counteracts anaemia amid iron deficiency or thalassaemia3,4 by acting as a gatekeeper of translation during erythroid differentiation, which has been attributed to its haem-binding ability5. Here we uncover that haem scarcity is sensed inside mitochondria through an OMA1-DELE1 axis. Mechanistically, haem deficiency triggers OMA1-dependent mitochondrial release of DELE1. In the cytosol, DELE1 releases inhibitory haem from HRI, which enables modifications in a crucial disordered segment of the kinase. We demonstrate that this sensor-actuator operates across human tissues, including erythroid progenitors, and is evolutionarily conserved down to bloodless invertebrates, thus predating the emergence of haemoglobin-based oxygen transport. Notably, pharmacological manipulation of this system enhances fetal globin expression-a central therapeutic objective in haemoglobinopathies. Together, these results reveal a primordial sentinel system that safeguards against haem-related toxicity from the single-cell to the organismic scale.
    DOI:  https://doi.org/10.1038/s41586-026-10885-x
  4. Curr Biol. 2026 Aug 03. pii: S0960-9822(26)00881-X. [Epub ahead of print]
    The mechanosensitive protein Zyxin influences Hippo signaling and tissue growth via adherens junctions and basal spot junctions in Drosophila.
    Harmanjeet Singh, Elliot Brooks, Connor Keegan, Kyoko Jinnai, Shu Kondo, Samuel A Manning, Benjamin Kroeger, Kieran F Harvey.
      Mechanical forces such as tension and compression play a central role in the growth and morphogenesis of tissues. Cell-cell junctions and the actin cytoskeleton are key mediators of mechanical forces and influence the activity of signaling networks, including the Hippo pathway. Here, we show that the mechanosensitive protein Zyxin (Zyx) localizes predominantly to adherens junctions (AJs) and basal spot junctions (BSJs) of Drosophila epithelial tissues. At these subcellular locations, Zyx works in concert with Ajuba to limit Hpo signaling and promote Drosophila epithelial tissue growth. Zyx recruits both Ajuba and the central Hpo pathway kinase Warts (Wts) to AJs and BSJs, which likely limits Wts activity by segregating it from Hpo pathway activator proteins. We further show that Zyx's association with cell-cell junctions is promoted by cytoskeletal tension and that Zyx supports the transmission of actomyosin tension to AJs in growing epithelial tissues. These findings indicate the conservation of this function. Thus, we provide new insights into how Zyx couples mechanical cues to Hpo pathway-dependent tissue growth and highlight the importance of BSJs and their associated actomyosin network in epithelial tissue development.
    Keywords:  Hippo signaling; LIM domain protein; Warts kinase; Zyxin; actomyosin; adherens junctions; basal spot junctions; cell adhesion; cytoskeletal tension; growth control
    DOI:  https://doi.org/10.1016/j.cub.2026.07.016
  5. Nature. 2026 Aug 05.
    ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.
    Qingwen Jiang, Manisha S Raghavan, Aileen M Rodriguez, Morgan Lallo, Cyrus L Tam, Saskia Hartner, Britney Forsyth, Ahmed Mahmoud, Fabian Zincke, Huiyong Zhao, Andrew Moorman, Sasha Balkaran, Kathleen Luckett, Jura Pintar, Yevgeniy Romin, Eric Chan, Anthony Santella, Bernadette Mödl, Farheen Shah, Ilyes Baali, Michael G Kharas, Elisa de Stanchina, Nil Urganci, Jinru Shia, Dana Pe'er, Francisco Sanchez-Vega, Richard Koche, Quaid Morris, Joseph M Chan, Karuna Ganesh.
      Phenotypic plasticity is a hallmark of cancer1; however the molecular switches required for cell-fate reprogramming are poorly understood. During intestinal wound-healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth2-10. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC11-15, is a pivotal stress-responsive orchestrator of dynamic dedifferentiation. In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, ZFP36L2 binds to stress-associated mRNAs that contain AU-rich 3' untranslated regions, which induces the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response. Together, these data show that ZFP36L2 acts as an important molecular switch that couples stress sensing with phenotypic plasticity. This in turn drives cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2-deficient CRC, the inability to re-enter the LGR5+ state during metastatic outgrowth promotes non-canonical lineage plasticity, which is associated with poor clinical outcomes.
    DOI:  https://doi.org/10.1038/s41586-026-10890-0
  6. EMBO J. 2026 Aug 05.
    Damage recognition by intestinal stem cells via Draper promotes adult Drosophila midgut regeneration.
    Martina Legido, Marie Srotyr, Rebecca Wafer, Parthive H Patel.
      Tissue regeneration after injury is crucial for restoring epithelial structure and function. Upon damage, a regenerative microenvironment forms that provides signalling cues that stimulate stem cell proliferation to replace lost cells. While this process is well understood, how stem cells themselves sense damage, translate this input into their proliferation and shape the regenerative microenvironment remains unclear. Here we show that Draper-Src-Shark signalling in Drosophila intestinal stem cells (ISCs) recognises tissue damage by sensing externalised phosphatidylserine on dying midgut epithelial cells and is required for STAT activation in ISCs to promote their proliferation. Unlike its role in phagocytosis, Draper in ISCs does not promote the clearance of these apoptotic enterocytes but rather facilitates ISC proliferation in the presence of damaged enterocytes. Moreover, Draper-Src-Shark signalling in progenitors regulates STAT transcriptional activity in the adjacent visceral muscle, indicating that progenitors can shape the regenerative microenvironment beyond tissue boundaries. As Src and STAT are also activated in the mammalian intestinal epithelium after damage and tumour formation, these findings may help develop therapies for tissue regeneration, inflammatory diseases and cancer.
    DOI:  https://doi.org/10.1038/s44318-026-00890-1
  7. Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00426-0. [Epub ahead of print]
    Coordination of ALT telomere maintenance across the cell cycle.
    Julia Vornberger, Matthias Altmeyer.
      Approximately 10%-15% of human cancers maintain their telomeres through alternative lengthening of telomeres (ALT), a recombination-based pathway that exploits chronic telomeric replication stress to drive telomere elongation. Although initiated in S phase, ALT-associated telomere synthesis is prominent in G2 phase and can extend into mitosis through mitotic DNA synthesis (MiDAS) and even into G1 phase of the next cell generation through post-mitotic DNA synthesis (post-MiDAS). Here, we review recent advances in the mechanistic understanding of ALT across the cell cycle. We emphasize how persistent replication stress and elevated DNA damage at telomeres drive ALT activity but must be tightly controlled to preserve telomere integrity and cell viability. We further highlight how MiDAS and post-MiDAS may act as last-resort pathways to preserve genome integrity when under-replicated telomeres bypass cell cycle checkpoints. Finally, we discuss how these mechanistic insights could be leveraged to develop novel therapeutic strategies specifically targeting ALT-dependent cancers.
    Keywords:  ALT; ATR; BIR; MiDAS; PML; SUMO; Telomeres; genome instability; post-MiDAS; replication stress
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.037
  8. Nature. 2026 Aug 05.
    An expanded codebook of human transcription factor DNA-binding specificity.
    Codebook Consortium
      Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs1. Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells2. Here we describe a systematic effort ('Codebook') to determine the sequence specificity of 332 putative and poorly characterized human TFs. More than 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177; 53%) of the TFs, of which most are associated with only a single protein. These results extend the vocabulary of sequence recognition encoded by human TFs by around 130 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched in cellular binding sites. Collectively, the data reveal tens of thousands of previously unknown, conserved and direct TF-binding sites across the human genome. These sites are concentrated in promoter regions and are predictive of gene expression. In summary, this new codebook provides an important step forward in decoding the human genome.
    DOI:  https://doi.org/10.1038/s41586-026-10798-9
  9. Nature. 2026 Aug 05.
    DCAF11-dependent molecular glue degrader activated by glutathionylation.
    Hojong Yoon, Franziska Wachter, Katharine A Barrett, Cyrus Jin, Anna Rodríguez-Pöhnlein, Justine C Rutter, Ryan J Lumpkin, Rebecca J Metivier, Katherine A Donovan, Kheewoong Baek, Yongying Jiang, Minwoo Lee, Robert W Kalis, Jianwei Che, Yuan Xiong, Eric S Fischer, Benjamin L Ebert.
      Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.
    DOI:  https://doi.org/10.1038/s41586-026-10873-1
  10. J Cell Biol. 2026 Oct 05. pii: e202602140. [Epub ahead of print]225(10):
    Volume EM reveals desmosome three-dimensional architecture in epithelial cells and tissue models.
    Navaneetha Krishnan Bharathan, William Giang, Eunice C Chen, Stephanie E Zimmer, Sonam Lhamo, Danielle M Jorgens, Jamie L Inman, Vito Mennella, Manfred Auer, Andrew P Kowalczyk.
      Desmosomes are cell-cell adhesive junctions present in cardiac tissues and epithelial tissues such as the epidermis. These junctions anchor to the intermediate filament cytoskeleton, providing mechanical integrity. Our understanding of desmosome architecture has largely been influenced by observations of two-dimensional images obtained through conventional electron microscopy. Here, using focused ion beam scanning electron microscopy, we report the three-dimensional ultrastructure of desmosomes in A431 epidermoid carcinoma and S1 human mammary epithelial cells. We also reveal differences in desmosome ultrastructure at homotypic and heterotypic junctions of human airway epithelial cells. Quantitative analyses of these datasets reveal variations in desmosome size, shape, and organization. Importantly, we report the presence of discontinuities or "gaps" within the outer dense plaque, a novel feature observed in either one or both desmosome halves. This study provides the first comprehensive description of the epithelial desmosome as a three-dimensional structure and emphasizes the need to investigate the effects of dynamic morphogenetic processes and disease states on desmosome ultrastructure.
    DOI:  https://doi.org/10.1083/jcb.202602140
  11. Development. 2026 08 01. pii: dev205485. [Epub ahead of print]153(15):
    A primitive endoderm-centric view of mammalian development.
    Rebecca P Kim-Yip, Denis F Faerberg, Eszter Posfai.
      The primitive endoderm (PE), or hypoblast in humans, is a conserved extra-embryonic lineage essential for mammalian development that fulfills key roles in embryo patterning, such as contributing to the gut endoderm, providing nutrient and gas exchange, and hosting the first wave of hematopoiesis. In this Review, we summarize our current understanding of PE development, focusing on the mouse and, where appropriate, the human context. We examine the molecular mechanisms involved in the segregation of the PE and epiblast lineages during pre-implantation development, exploring how stochastic processes and positional history initiate fate specification, and how robust ratio control of the two lineages is ensured. Furthermore, we evaluate the expanding repertoire of in vitro stem cell models of embryos, categorizing them according to their PE representation and functional utility in studying peri- and post-implantation development.
    Keywords:  Extra-embryonic; Mammalian development; Primitive endoderm; Yolk sac
    DOI:  https://doi.org/10.1242/dev.205485
  12. Nat Rev Mol Cell Biol. 2026 Aug 03.
    Structure and function of the centromere and inner kinetochore.
    Rae R Brown, Pim J Huis In 't Veld, Andrea Musacchio, Aaron F Straight.
      Accurate chromosome segregation in eukaryotic cells ensures that each daughter cell receives the same chromosome complement during cell division. Key to this process is the kinetochore, a macromolecular complex that connects spindle microtubules to the chromosome. The kinetochore is composed of a diverse array of proteins that can be broadly separated into an inner and outer kinetochore. Each chromosome also contains a distinct site that specifies the location of kinetochore formation, the centromere, which in many species is epigenetically defined by the specialized histone H3 variant centromere protein A (CENP-A). In this Review, we discuss recent advances in determining the complete structure and function of the inner kinetochore, as well as the sequence and 2D and 3D organization of centromeric chromatin. We discuss the implications of these recent advances for our understanding of the assembly and function of the inner kinetochore. We refer readers to a complementary review published in the same issue for a discussion on the structure and function of the outer kinetochore. Finally, we outline key questions persisting in the field driving future studies of the kinetochore and centromere.
    DOI:  https://doi.org/10.1038/s41580-026-00989-7
  13. Science. 2026 Aug 06. 393(6811): 601-606
    A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.
    Christina Gladkova, Maria G Paez-Segala, William P Grant, Mark Kittisopikul, Samuel A Myers, Yuxiao Wang, Ronald D Vale.
      The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.
    DOI:  https://doi.org/10.1126/science.aeh1475
  14. Sci Adv. 2026 Aug 07. 12(32): eaec9545
    High-resolution mapping of embryonic genome activation unveils a decoupling of transcription activation from precocious H3K4me3 removal.
    Jasmina Al-Mousawi, Luca Michetti, Laura Castaldi, Na Liu, Laura Villacorta, Vladimir Benes, Ana Boskovic.
      The lack of temporal resolution in transcriptomic data during mammalian embryonic genome activation (EGA) has precluded the comprehensive understanding of the functional relationships between the various gene regulatory mechanisms governing this process. Here, we finely dissect the transcriptional dynamics of mouse EGA using precision in vitro fertilization (IVF) coupled with single-embryo RNA sequencing. Our highly temporally resolved dataset uncovers an extensive, step-wise remodeling of the embryonic messenger RNA landscape, affecting ∼30% of the total detectable transcripts over a 9-hour time frame. We capture the gradual shift from maternal to embryonic messenger RNAs, successfully identify ribosome biogenesis and translation as hallmarks of EGA, and find previously unidentified gene expression dynamics. We further uncover a set of eight histone demethylating enzymes among the earliest up-regulated EGA genes and leverage our precision-IVF to dissect the transcriptional versus developmental impact of histone H3 lysine-4 trimethylation (H3K4me3) remodeling after fertilization. Our results indicate that precocious removal of H3K4me3 from embryonic chromatin only modestly affects embryonic transcription without perturbing EGA timing, arguing against a major instructive role of precocious remodeling of maternally inherited H3K4me3 after fertilization on genome activation. High-resolution transcriptome mapping coupled with functional perturbations allows us to distinguish direct gene expression effects from general impacts on developmental timing, opening avenues for further quantitative characterization of the impact of epigenome remodeling on embryonic transcription.
    DOI:  https://doi.org/10.1126/sciadv.aec9545
  15. Mol Cell. 2026 Aug 05. pii: S1097-2765(26)00509-5. [Epub ahead of print]
    α-Satellite RNA maintains centromeric cohesion through R-loops.
    Lu Yang, Qian Zhang, Zhen Teng, Erin Moran, Zhen Lin, P Todd Stukenberg, Hong Liu.
      Tandemly repeated satellite DNAs provide the building blocks for centromeres, but whether and how their transcripts regulate chromosome segregation remain poorly defined. Here, we show that human α-satellite RNAs (α-SatRNAs) are required for maintaining centromeric cohesion during mitosis. α-SatRNAs localize to centromeres and physically associate with α-satellite chromatin to form R-loops both in cis and in trans. Disruption of these R-loops by RNase H1 overexpression causes centromeric cohesion defects, phenocopying α-SatRNA knockdown, which can be rescued by the expression of an α-satellite consensus sequence, supporting a major role for α-SatRNA-formed R-loops in centromeric cohesion. Furthermore, ectopic targeting of the cohesion protector Shugoshin (Sgo)1 to centromeric α-SatDNAs largely rescues centromeric cohesion defects caused by α-SatRNA knockdown or RNase H1 overexpression. Our findings reveal a critical pathway comprising α-SatRNAs, R-loops, and Sgo1 in regulating centromeric cohesion, thus providing an important mechanism to explain how satellite transcripts regulate chromosomal stability.
    Keywords:  R-loops; centromere; centromeric cohesion; chromosome segregation; α-satellite RNA
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.023
  16. Circ Res. 2026 Aug 07.
    CDK5RAP3-Mediated Mitochondrial RQC Alleviates Pathological Cardiac Hypertrophy.
    Yazhi Peng, Wenwen Cai, Tailai Du, Yi Zheng, Yiling Yao, Gang Dai, Jialing Wu, Yan Li, Jiangui He, Yugang Dong, Jing-Song Ou, Chen Liu, Xin He, Zhan-Peng Huang.
       BACKGROUND: Recent studies have revealed heterogeneity among ribosomes. Pathological cardiac hypertrophy is characterized by profound alterations in translation. However, how ribosome heterogeneity contributes to this process remains largely unclear.
    METHODS: We used translating ribosome affinity purification coupled with mass spectrometry to profile ribosome-interacting proteins. Cardiomyocyte-specific gene manipulation was achieved through either genetic knockout or adeno-associated virus-mediated overexpression. Pathological cardiac hypertrophy was induced by transverse aortic constriction surgery in vivo and by phenylephrine stimulation in vitro.
    RESULTS: The cardiomyocyte-specific ribosome proteomics indicated dynamic alterations in ribosome-interacting proteins during pathological hypertrophy. Notably, multiple proteins associated with ribosome stalling were detected in the ribosome-interactome of hypertrophic hearts. Among these, we verified that CDK5RAP3 (CDK5 regulatory subunit-associated protein 3) exhibited the most specific ribosome binding in hypertrophic hearts. CDK5RAP3 was upregulated and recruited to ribosomes during pathological hypertrophy. It promoted RPL26 (ribosomal protein L26) UFMylation and ribosome-associated quality control on the mitochondrial surface. In vitro, CDK5RAP3 knockdown exacerbated cardiomyocyte hypertrophy induced by phenylephrine, whereas its overexpression attenuated it. In vivo, cardiomyocyte-specific CDK5RAP3 knockout promoted, while adeno-associated virus-mediated overexpression suppressed pathological cardiac hypertrophy induced by transverse aortic constriction. Mechanistically, ribosome stalling on the mitochondrial surface was exacerbated in hypertrophic hearts of both humans and mice, which was associated with impaired mitochondrial protein import. CDK5RAP3 enhanced ribosome-associated quality control, alleviated ribosome stalling, and restored mitochondrial protein import, thereby improving mitochondrial function. Notably, mitochondrial import of PDP1 was maintained by CDK5RAP3-mediated ribosome-associated quality control. Knockdown of PDK (pyruvate dehydrogenase kinase) 1/2, functional antagonists of PDP1, reversed cardiomyocyte hypertrophy caused by CDK5RAP3 deficiency.
    CONCLUSIONS: This study identifies CDK5RAP3-mediated ribosome-associated quality control on the mitochondrial surface as a critical protective mechanism that preserves protein import and mitochondrial function during pathological cardiac hypertrophy.
    Keywords:  cardiomegaly; endoplasmic reticulum; heart failure; mitochondria; pyruvate kinase
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.328184
  17. Nat Cell Biol. 2026 Aug 06.
    Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis.
    Jayna J Mistry, Kira A Young, Anna Navarro Figueredo, Gibran Edun, Alicia G Aguilar-Navarro, Patricia A Colom Díaz, Maria Telpoukhovskaia, Inés Fernández Maestre, Sheng F Cai, Katharina S Götze, Anastasia N Tikhonova, Ross L Levine, Jennifer J Trowbridge.
      Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.
    DOI:  https://doi.org/10.1038/s41556-026-02025-4
  18. J Cell Biol. 2026 Sep 07. pii: e202601131. [Epub ahead of print]225(9):
    STAT5A-α-actinin axis links actin integrity to mitochondrial homeostasis and innate immune activation.
    Boyue Sun, Mathumathi Krishnamohan, Reinat Nevo, Eyal Zoler, Yael Elbaz-Alon, Benjamin Geiger, Gideon Schreiber.
      STAT5A is unique in its diverse expression in different cells. Here, we show that STAT5A deficiency results in reduced expression of the actin-bundling protein α-actinin-1, which alters cytoskeletal reorganization, including loss of actin bundles, reduction of cellular motility, and clustering of mitochondria and endoplasmic reticulum in the perinuclear region. These changes in cellular architecture led to production of ROS by the mitochondria, which may be explained by reduced peroxisome abundance. This, in turn, results in dsDNA breaks and formation of cytoplasmic micronuclei, and activating the cGAS-STING pathway, and mediating type I IFN production and the expression of IFN-stimulated genes. The ectopic expression of α-actinin-1 or STAT5A in STAT5A knockout cells is sufficient to restore actin bundle formation and nullifies all downstream effects. Conversely, inhibiting downstream steps suppresses only subsequent events in the pathway. STAT5A knockout results in a similar phenotype as seen with cytochalasin B, an inhibitor of actin polymerization. Overall, we show that STAT5A-α-actinin-1 links cytoskeleton integrity to mitochondrial immune regulation.
    DOI:  https://doi.org/10.1083/jcb.202601131
  19. Nat Cell Biol. 2026 Aug 05.
    BRD4 recruitment into HP1 condensates desilences transcription without erasure of repressive chromatin.
    Christopher J Brandon, Sarah Robinson-Thiewes, Mangesh Kaulage, Wojciech Rosikiewicz, Matthew J Cuneo, Joseph Brett, Jindpreet Kandola, Walter H Lang, Jonathan Low, Ashraf Mohammed, Adithi Danda, Sam Rider, Marcus Valentine, Jason Ochoada, Brandon Young, Theresa Nguyen, Sandra J Kietlinska, Aaron B Taylor, Burkhard Hoeckendorf, Patrick Rodrigues, Wenwei Lin, Khaled Khairy, Beisi Xu, Anang A Shelat, Taosheng Chen, Tanja Mittag, Aseem Z Ansari.
      How genes are desilenced without erasure of repressive chromatin is a poorly understood phenomenon. A dominant mode of repression occurs through methylation of lysine 9 of histone H3 (H3K9me3), a mark that engages heterochromatin protein 1 (HP1) to drive chromatin compaction and transcriptional silencing. The erasure and replacement of this repressive mark with acetyl/acyl groups recruits positive factors such as BRD4/BET to elicit gene transcription. Here we report that, in Friedreich's ataxia, a synthetic gene regulator (SynGR1/SynTEF1) licenses transcription across repressive chromatin without removal or replacement of H3K9me3 or HP1. By recruiting BRD4/BET into repressive GAA repeats in frataxin (FXN), SynGR1 creates a paradoxical state wherein gene transcription and repressive chromatin coexist. Contrary to convention, we find that BRD4 partitions into phase separated HP1 condensates in vitro and into HP1 puncta in patient-derived cells, thus offering a mechanistic explanation for desilencing transcription without the dispersal of mesoscale repressive chromatin. More broadly, our study highlights the dynamic nature of repressive chromatin and the context dependence of epigenetic marks in regulating gene expression.
    DOI:  https://doi.org/10.1038/s41556-026-02044-1
  20. Semin Cell Dev Biol. 2026 Aug 05. pii: S1084-9521(26)00022-4. [Epub ahead of print]184 103688
    A metabolic view of gastrulation: Coordinating signalling, epigenetics and morphogenesis.
    Tatiana Firfa, Tamara Civetta, Eunice HoYee Chan, Kristina S Stapornwongkul.
      Gastrulation is the morphogenetic process by which the single-layered pluripotent epiblast is reorganised into the three germ layers and the basic body plan is established. While the metabolic state of pluripotent stem cells is well characterised, the metabolic remodelling that coincides with germ layer specification is less well understood. Emerging evidence suggests that metabolism functions as more than a passive housekeeping process and instead acts as a dynamic regulator of cell state during these developmental transitions. Here, we review recent work that implicates a role for metabolic pathways in regulating cell fate and morphogenesis during gastrulation. In particular, glucose metabolism appears to serve as a critical regulatory layer, modulating morphogen signalling to promote the emergence and function of mesodermal and endodermal populations. We also discuss the role of the tricarboxylic acid cycle and one-carbon metabolism in epigenetic remodelling and highlight the role of lipid metabolism in coupling the biophysical properties of membranes to cellular identity and morphogenetic movements. A current challenge is to distinguish in which situations metabolic shifts act as instructive drivers or permissive gatekeepers of development. Technological advances in spatial metabolomics, biosensors, and optogenetics are now facilitating the visualisation and manipulation of metabolic activity, paving the way for a mechanistic understanding of how metabolism shapes cell fate and behaviour during gastrulation.
    Keywords:  EMT; Energetics; Epimetabolites; Gastrulation; Germ layer specification; Metabolic signalling; Metabolism
    DOI:  https://doi.org/10.1016/j.semcdb.2026.103688
  21. Nat Cell Biol. 2026 Aug 07.
    The mitochondria enzyme OGDH defends against disulfidptosis by licensing METTL3-regulated NRF2 translation.
    Xiao-Yan Chen, Ke-Jun Xu, Jia-Xin Zhou, Liu-Zheng Wu, De-Yi Feng, Yun-Feng Guan, Heng-Hui Li, Guang-Xi Yang, Yu Qian, Meng-Hao Mi, Sheng-Fu Wu, Zhi-Yuan Zhang, Qi-Tao Chen, Bo Zhou, Hang-Zi Chen.
      Disulfidptosis is a form of regulated cell death triggered by disulfide stress resulting from glucose starvation. The capacity to evade disulfidptosis is crucial for tumour cells to withstand glucose-limited environments. Here we demonstrate that OGDH, a rate-limiting enzyme in citric acid cycle, is critical for conferring resistance to disulfidptosis. High expression of HSPA9 in melanoma protects OGDH from glucose deprivation-induced oxidative inactivation, thereby ensuring OGDH-generated succinyl-CoA for METTL3 succinylation. Succinylated METTL3 recognizes m6A modification on NRF2 mRNA to license NRF2 translation, TrxR1 expression and subsequent evasion of disulfidptosis. Combined suppression of HSPA9 and glucose uptake inhibits melanoma growth in mouse models. In patients with melanoma, expressions of HSPA9 and OGDH negatively correlate with the disulfidptosis signature and are associated with an unfavourable clinical prognosis. Therefore, our findings not only highlight the dependence of melanoma cells on the HSPA9-OGDH-METTL3-NRF2 axis for disulfidptosis evasion, but also propose a combined intervention strategy for melanoma therapy.
    DOI:  https://doi.org/10.1038/s41556-026-02042-3
  22. Genes Dev. 2026 Aug 03. 40(15-16): 1227-1249
    LKB1 functions as a checkpoint for neuronal-glial balance during enteric nervous system development.
    Anthony Lucas, Florence Appaix, Jordan Allard, Marie Mével-Aliset, Anca G Radu, Florence Fauvelle, Bertrand Favier, Alexei Grichine, Jochen Maurer, Pierre Hainaut, Laura Attardi, Marc Billaud, Sakina Torch, Chantal Thibert.
      How the energy status of enteric progenitors controls neurogliogenesis and the subsequent formation of the complex enteric nervous system (ENS) remains poorly understood. We previously showed that the tumor suppressor kinase LKB1 is essential for postnatal ENS maintenance through amino acid homeostasis. Here, we investigated LKB1's functions during embryonic ENS formation using a genetically engineered mouse model with conditional Lkb1 inactivation in neural crest progenitors during gut colonization. Using advanced 3D imaging techniques on cleared tissue including light sheet microscopy and adaptive optics confocal microscopy, we found that Lkb1 loss impairs early neuronal differentiation followed by progressive glial degeneration, leading to hypoganglionosis and compromised digestive tissue integrity. Notably, Lkb1 inactivation induced a transient upregulation of the glial stress marker S100β during gestation, suggestive of a reactive glial state preceding glial loss. Consistent with this response, Lkb1 loss elevated oxidative stress in the digestive tract and in neural crest progenitors and their glial derivatives, triggering DNA damage and p53 activation. Although p53 ablation rescued glial specification in vitro and glial maintenance in vivo, it only partially restored ENS architecture in vivo without rescuing enteric neuron numbers. Together, these findings establish LKB1 as a critical metabolic checkpoint governing neuronal-glial balance during ENS development and suggest that dysregulated LKB1 signaling may contribute to human enteric neurogliopathies.
    Keywords:  ROS and p53 activation; digestive tissue integrity; enteric nervous system; expression; neuronal–glial formation; vagal neural crest cells
    DOI:  https://doi.org/10.1101/gad.353358.125
  23. Cell. 2026 Aug 06. pii: S0092-8674(26)00811-1. [Epub ahead of print]189(16): 4832-4856
    Why studying females reveals more about aging: The reproductive resilience hypothesis for the evolution of sex-specific aging.
    Parminder Singh, Vineeta Tanwar, Yifan Xiang, Lizbeth Enriquez Najera, Steven N Austad, Pankaj Kapahi.
      Classical evolutionary theories of aging, including antagonistic pleiotropy (AP) and the disposable soma theory (DST), explain why aging exists but are often applied without considering how sex-specific reproductive strategies shape the forces of natural selection on survival. They do not explain why females consistently outlive males across taxa, despite their greater reproductive investment, or why in some contexts, such as eusocial queens, extraordinary fecundity is coupled with exceptional longevity. To explain these patterns, we propose the reproductive resilience hypothesis (RRH), which posits that when reproductive success depends on prolonged survival and caregiving, natural selection favors coupling reproduction with enhanced somatic maintenance rather than trading it off. We suggest that reproductive events, including age at sexual maturity, pregnancy, lactation, and menopause, are pivotal life-history transitions and must be explicitly integrated into studies of sex differences that drive aging and susceptibility to age-related diseases. We further propose that loss of reproductive resilience is a sex-specific hallmark of aging that coordinates the emergence of multiple downstream hallmarks, helping explain the acceleration of systemic aging and age-related disease following reproductive decline. We propose that, for these reasons, studying females should be prioritized, as it has unique implications for discovering pathways to slow aging and prevent age-related diseases, ultimately benefiting both women and men.
    DOI:  https://doi.org/10.1016/j.cell.2026.07.013
  24. Mol Biol Cell. 2026 Aug 05. mbcE26010052
    Vimentin bridges scales to convert polarized cell locomotion into coordinated collective migration.
    Sudheer Kumar Peneti, Satish Babu Morparthi, Clémence Thiant, Joseph d' Alessandro, Lucas Anger, Ranjith Chilupuri, Tien Dang, Manon Arnaud, Julia Eckert, Stéphane Vassilopoulos, Benoit Ladoux, René-Marc Mège.
      Collective cell migration is central in development and disease. Vimentin is an intermediate filament protein expressed by epithelial cells at the edge of wounds where collective cell migration is most efficient. Yet, its functional role in this context remains underexplored. Here, we show that vimentin, over-expressed in cells undergoing partial epithelial to mesenchymal transition at the edge of epithelial monolayers, has a multiscale impact on the whole monolayer mechano-dynamics. Vimentin knock-down delays wound closure, reduces cell coordination, while increasing traction forces exerted by cells on the substratum. It also disrupts the directionality of leader cells migration, as well as the cohesion and coordinated motion of cells deep in the monolayer. We further show that vimentin promotes the conversion of polarized cell locomotion into coordinate collective migration by polarizing actin, focal adhesions and traction forces, sustaining leader cell's lamellipodium protrusive activity and directionality, while allowing mechanical coupling of leader with follower cells. Altogether, we show that vimentin is essential for bridging polarized single cell locomotion and coordinated collective migration to allow efficient collective migration. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E26-01-0052
  25. Nat Cardiovasc Res. 2026 Aug 06.
    Reducing the mechanical load reawakens adult cardiomyocyte proliferation.
      
    DOI:  https://doi.org/10.1038/s44161-026-00845-z
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒28 at 4:11.