bims-ginsta Biomed News
on Genome instability
Issue of 2026–02–01
34 papers selected by
Jinrong Hu, National University of Singapore
  1. Transient proliferation by reversible YAP and mitogen control of the cyclin D1/p27 ratio.
  2. Robust cytoplasmic partitioning by solving a cytoskeletal instability.
  3. Subcellular mass spectrometry reveals proteome remodeling in an asymmetrically dividing (frog) embryonic stem cell.
  4. Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during mouse skeletal muscle regeneration.
  5. Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming.
  6. A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis.
  7. Airway injury induces alveolar epithelial responses mediated by macrophages.
  8. Mechanical force locally damages, remodels, and stabilizes the lattice of spindle microtubules.
  9. Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
  10. Actomyosin cortex integration with complex plasma membrane topography in the early Drosophila embryo.
  11. Molecular requirements for PLK1 activation by T-loop phosphorylation.
  12. Biomolecular condensates sustain pH gradients at equilibrium through charge neutralization.
  13. Metabolically regulated proteasome supramolecular organization in situ.
  14. Lysosomes as hubs of metabolic sensing and cellular homeostasis.
  15. TORC1-dependent translation drives chromatin remodeling during the germ-cell-to-maternal transition in Drosophila.
  16. Heritability of intrinsic human life span is about 50% when confounding factors are addressed.
  17. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.
  18. Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
  19. DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
  20. Ribosome-NAC collaboration: A regulatory platform for cotranslational chaperones, enzymes, and targeting factors.
  21. Molecular basis for the activation of Aurora A and Plk1 kinases during mitotic entry.
  22. Dimerization-dependent gel-like condensation with dsDNA underpins the activation of human cGAS.
  23. Putting mammalian early embryonic cells into dormancy.
  24. PAF15-PCNA exhaustion governs the strand-specific control of DNA replication.
  25. NuMA promotes constitutive heterochromatin compaction by stabilizing linker histone H1 on chromatin.
  26. GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.
  27. Proteomic profiling of UV damage repair patches uncovers histone chaperones with central functions in chromatin repair.
  28. Single-cell proteomic landscape of the developing human brain.
  29. Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
  30. Scalable and multiplexed recorders of gene regulation dynamics across weeks.
  31. Cellular survivorship bias as a mechanistic driver of muscle stem cell aging.
  32. The kinetochore corona orchestrates chromosome congression through transient microtubule interactions.
  33. Elucidating chiral myosin-induced actin dynamics: From single-filament behavior to collective structures.
  34. Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
  1. Commun Biol. 2026 Jan 29.
    Transient proliferation by reversible YAP and mitogen control of the cyclin D1/p27 ratio.
    Katherine R Ferrick, Samsara W Upadhya, Yilin Fan, Nalin Ratnayeke, Mary N Teruel, Tobias Meyer.
      Hippo-YAP signaling orchestrates transient proliferation during tissue repair and is therefore an attractive target in regenerative medicine. However, it is unclear how YAP integrates mitogen and contact signals to start and stop proliferation. Here we show that reduced contact inhibition, increased mitogen signaling, and YAP-TEAD activation converge on increasing the nuclear cyclin D1/p27 protein ratio during early G1 phase, towards a threshold ratio that dictates whether individual cells enter or exit the cell cycle. YAP increases this ratio in concert with inducing mitogen signaling, by increasing EGFR and other receptors that signal primarily through ERK. After a delay, contact inhibition suppresses YAP activity, which gradually downregulates mitogen signaling and the cyclin D1/p27 ratio. Thus, critical for regeneration without cancer initiation, robust proliferation responses result from a YAP-induced and receptor-mediated prolonged increase in the cyclin D1/p27 ratio, which is reversed by delayed suppression of receptor signaling after contact inhibition of YAP.
    DOI:  https://doi.org/10.1038/s42003-026-09590-2
  2. Nature. 2026 Jan 28.
    Robust cytoplasmic partitioning by solving a cytoskeletal instability.
    Melissa Rinaldin, Alison Kickuth, Adam Lamson, Benjamin Dalton, Yitong Xu, Pavel Mejstřík, Stefano Di Talia, Jan Brugués.
      Early development across vertebrates and insects critically relies on robustly reorganizing the cytoplasm of fertilized eggs into individualized cells1,2. This intricate process is orchestrated by large microtubule structures that traverse the embryo, partitioning the cytoplasm into physically distinct and stable compartments3,4. Here, despite the robustness of embryonic development, we uncover an intrinsic instability in cytoplasmic partitioning driven by the microtubule cytoskeleton. By combining experiments in cytoplasmic extract and in vivo, we reveal that embryos circumvent this instability through two distinct mechanisms: either by matching the cell-cycle duration to the time needed for the instability to unfold or by limiting microtubule nucleation. These regulatory mechanisms give rise to two possible strategies to fill the cytoplasm, which we experimentally demonstrate in zebrafish and Drosophila embryos, respectively. In zebrafish embryos, unstable microtubule waves fill the geometry of the entire embryo from the first division. Conversely, in Drosophila embryos, stable microtubule asters resulting from reduced microtubule nucleation gradually fill the cytoplasm throughout multiple divisions. Our results indicate that the temporal control of microtubule dynamics could have driven the evolutionary emergence of species-specific mechanisms for effective cytoplasmic organization. Furthermore, our study unveils a fundamental synergy between physical instabilities and biological clocks, uncovering universal strategies for rapid, robust and efficient spatial ordering in biological systems.
    DOI:  https://doi.org/10.1038/s41586-025-10023-z
  3. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2518372123
    Subcellular mass spectrometry reveals proteome remodeling in an asymmetrically dividing (frog) embryonic stem cell.
    Bowen Shen, Leena R Pade, Fei Zhou, Peter Nemes.
      Subcellular proteomics maps protein localization within restricted domains of a cell, complementing high-resolution imaging by expanding the number of proteins that can be profiled at once. Achieving this at depth from subcellular inputs remains challenging. Here, we advance microprobe capillary electrophoresis-mass spectrometry (CE-MS) with trapped ion mobility spectrometry and data-independent acquisition (diaPASEF) to quantify more than a thousand proteins from opposite poles of an asymmetrically dividing embryonic blastomere in live Xenopus laevis embryos. From ~200 pg of HeLa digest-approximately 80% of a cell-the technology identified 1,035 proteins with high reproducibility in quantification (coefficient of variation <15% across technical triplicates). With microprobe sampling in vivo, we quantified 808-1,022 proteins from opposite poles of the dorsal-animal (D1) blastomere before division, and we traced how these spatial distributions are retained or remodeled in the descendant D1.1 (neural-fated) and D1.2 (epidermal-destined) cells. To decouple subcellular distributions from dorsal-ventral axis cues, we perturbed patterning by ultraviolet ventralization. These results establish microprobe CE-MS for deep subcellular proteomics in intact embryos and reveal spatially distinct protein distributions during early fate specification. These spatial proteome differences appear consistent with early lineage tendencies yet precede and likely bias, rather than fix, later fate decisions that depend on gastrula-stage inductive signals.
    Keywords:  Xenopus; blastomere; mass spectrometry; proteomics; subcellular
    DOI:  https://doi.org/10.1073/pnas.2518372123
  4. Elife. 2026 Jan 29. pii: RP103550. [Epub ahead of print]14
    Branched actin polymerization drives invasive protrusion formation to promote myoblast fusion during mouse skeletal muscle regeneration.
    Yue Lu, Tezin Walji, Pratima Pandey, Chuanli Zhou, Christa W Habela, Scott B Snapper, Rong Li, Elizabeth H Chen.
      Skeletal muscle regeneration is a multistep process involving the activation, proliferation, differentiation, and fusion of muscle stem cells, known as satellite cells. Fusion of satellite cell-derived myoblasts (SCMs) is indispensable for generating the multinucleated, contractile myofibers during muscle repair. However, the molecular and cellular mechanisms underlying SCM fusion during muscle regeneration remain incompletely understood. Here, we reveal a critical role for branched actin polymerization in SCM fusion during mouse skeletal muscle regeneration. Using conditional knockouts of the Arp2/3 complex and its actin nucleation-promoting factors N-WASP and WAVE, we demonstrate that branched actin polymerization is specifically required for SCM fusion but dispensable for satellite cell proliferation, differentiation, and migration. We show that the N-WASP and WAVE complexes have partially redundant functions in regulating SCM fusion and that branched actin polymerization is essential for generating invasive protrusions at fusogenic synapses in SCMs. Together, our study identifies branched-actin regulators as key components of the myoblast fusion machinery and establishes invasive protrusion formation as a critical mechanism enabling myoblast fusion during skeletal muscle regeneration.
    Keywords:  Arp2/3 complex; branched actin polymerization; developmental biology; invasive protrusions; mouse; myoblast fusion; regenerative medicine; satellite cells; skeletal muscle regeneration; stem cells
    DOI:  https://doi.org/10.7554/eLife.103550
  5. Nat Metab. 2026 Jan 28.
    Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming.
    Yinuo Wang, Haojie Shi, Janina Wittig, Yonggang Ren, Julio Cordero, Matthias Dewenter, Jessica Mella, Abigail Buchwalter, Johannes Backs, Thomas Wieland, Joerg Heineke, Ingrid Fleming, Sofia-Iris Bibli, Gergana Dobreva.
      Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01443-2
  6. Cell. 2026 Jan 28. pii: S0092-8674(25)01478-3. [Epub ahead of print]
    A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis.
    Gabriella N L Chua, Emily C Beckwitt, Victoria Miller-Browne, Olga Yurieva, Dan Zhang, Bryce J Katch, Nina Y Yao, John W Watters, Kaitlin Abrantes, Ryogo Funabiki, Xiaolan Zhao, Michael E O'Donnell, Shixin Liu.
      The ring-shaped sliding clamp proliferating cell nuclear antigen (PCNA) enables DNA polymerases to perform processive DNA synthesis during replication and repair. The loading of PCNA onto DNA is catalyzed by the ATPase clamp-loader replication factor C (RFC). Using a single-molecule platform to visualize the dynamic interplay between PCNA and RFC on DNA, we unexpectedly discovered that RFC continues to associate with PCNA after loading, contrary to the conventional view. Functionally, this clamp-loader/clamp (CLC) complex is required for processive DNA synthesis by polymerase ẟ (Polẟ), as the PCNA-Polẟ assembly is inherently unstable. This architectural role of RFC is dependent on the BRCA1 C-terminal homology (BRCT) domain of Rfc1, and mutation of its DNA-binding residues causes sensitivity to genotoxic stress in vivo. We further showed that flap endonuclease I (FEN1) can also stabilize the PCNA-Polẟ interaction and mediate robust synthesis. Overall, our work revealed that, beyond their canonical enzymatic functions, PCNA-binding proteins harbor non-catalytic functions important for DNA replication and genome maintenance.
    Keywords:  DNA damage; DNA replication; FEN1; Okazaki fragment; PCNA; Polδ; RFC; clamp loader; genome maintenance; sliding clamp
    DOI:  https://doi.org/10.1016/j.cell.2025.12.029
  7. Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01653-5. [Epub ahead of print]45(2): 116881
    Airway injury induces alveolar epithelial responses mediated by macrophages.
    Irene G Wong, Margherita Paschini, Jillian Stark, Alan Baez Vazquez, VanNashlee Ya, Aaron L Moye, Susanna M Dang, Maria F Trovero, Emma L Thompson, Sidrah Ahmed, Fatima N Chaudhry, Andrea Shehaj, Maral J Rouhani, Roderick Bronson, Sam M Janes, Samuel P Rowbotham, Jarod A Zepp, Ruth A Franklin, Carla F Kim.
      Airway injury activates local progenitors and stimulates cell-cell interactions to restore homeostasis, but it is unknown how distal niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar and immune responses. Single-cell transcriptomics and in vivo validation of mouse models of airway-specific epithelial injury revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific injury or ablation. Myeloid cells exhibited altered gene expression after club cell loss and were detectable in the bronchoalveolar lavage fluid. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) exhibiting an injury-induced gene expression program. Overall, these results demonstrate that acute airway damage can trigger myeloid-mediated lung alveolar responses that may contribute to disease susceptibility or dysfunction.
    Keywords:  AT2; CP: immunology; airway injury; alveolar macrophages; club cells; lung stem cells; naphthalene
    DOI:  https://doi.org/10.1016/j.celrep.2025.116881
  8. Curr Biol. 2026 Jan 23. pii: S0960-9822(25)01700-2. [Epub ahead of print]
    Mechanical force locally damages, remodels, and stabilizes the lattice of spindle microtubules.
    Caleb J Rux, Megan K Chong, Valerie Myers, Nathan H Cho, Sophie Dumont.
      To segregate chromosomes at cell division, the spindle must maintain its structure under force. How it does so remains poorly understood. To address this question, we use microneedle manipulation to apply local force to spindle microtubule bundles, kinetochore fibers (k-fibers), inside mammalian cells. We show that local load directly fractures k-fibers and that newly created plus-ends often have arrested dynamics, resisting depolymerization. Force alone, without fracture, is sufficient for spindle microtubule stabilization, as revealed by laser ablating k-fibers under local needle force. Doublecortin, which binds a compacted microtubule lattice, is lost around the force application site, suggesting local force-induced structural remodeling. In turn, end-binding protein 1 (EB1), which recognizes guanosine triphosphate (GTP)-tubulin, is locally enriched at stabilization sites, both before and after force-induced fracture. Together, our findings support a model in which force-induced damage leads to local spindle microtubule lattice remodeling and stabilization, which we propose reinforces the spindle where it experiences critical loads.
    Keywords:  cell division; force; mechanics; microneedle manipulation; microtubule; mitosis; repair; spindle
    DOI:  https://doi.org/10.1016/j.cub.2025.12.047
  9. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00027-4. [Epub ahead of print]
    Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
    Isabella R Lawrence, Emily C Sutton, Shivang Bhaskar, Susan J Baserga.
      Ribosome biogenesis is a complex, multi-step cellular process that begins in the nucleolus and produces ribosomes that translate mRNA into proteins in the cytoplasm. This process is essential for cellular growth yet is resource intensive. It is therefore tightly coordinated with cytoplasmic requirements, energy availability, and the cell cycle through several kinase signaling pathways. Increasing evidence indicates that proteins shared between the cytoplasm and nucleolus may enhance this coordination. Here, we evaluate the interplay between the cytoplasm and nucleolus in human cells, presenting an intricate bidirectional regulatory network with emerging clinical relevance. We describe the phosphorylation events that promote ribosome biogenesis during interphase, focusing on mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase (ERK), and casein kinase II (CK2). By contrast, protein phosphorylation inactivates ribosome biogenesis during mitosis. We further summarize several factors shared among the mitotic machinery, cytoplasmic organelles, and the nucleolus. Moreover, we highlight the mounting evidence that dysregulated cytoplasmic-nucleolar feedback contributes to the progression of several diseases.
    Keywords:  cancer; endoplasmic reticulum; lysosome; mTOR; mitochondria; mitosis; muscle atrophy; rRNA; ribosome biogenesis; ribosomopathies
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.007
  10. J Cell Biol. 2026 Apr 06. pii: e202509151. [Epub ahead of print]225(4):
    Actomyosin cortex integration with complex plasma membrane topography in the early Drosophila embryo.
    Rowan K Naidoo, Rebecca Tam, Tony J C Harris.
      Most animal cells display widespread plasma membrane (PM) folding. It is unclear how cortical tension is generated and controlled over cell surfaces with such PM topography. Our results highlight the early syncytial Drosophila embryo as a model of cortical actomyosin network integration with complex PM topography. Over the embryo surface, before arrival of peripheral nuclei, actomyosin networks entwine across a dense field of PM infoldings. Actomyosin network and PM topography changes are closely coupled during synchronous mitotic cycles and following experimental perturbations. Actomyosin activity is required for periods of condensed spacing between PM infoldings, when the integration of actomyosin networks and PM topography seems to form a tensile, composite material. These cyclic condensations are preceded by periods of expanded spacing between PM infoldings driven by Arp2/3 activity. Without Arp2/3 activity, the actomyosin cortex and PM topography gain an aberrant configuration, excessive tension is evident, and embryo surface distortions occur. Overall, PM topography seems integral to actomyosin cortex function and regulation.
    DOI:  https://doi.org/10.1083/jcb.202509151
  11. EMBO J. 2026 Jan 28.
    Molecular requirements for PLK1 activation by T-loop phosphorylation.
    Arianna Esposito-Verza, Duccio Conti, Paulo D Rodrigues Pedroso, Lina Oberste-Lehn, Carolin Koerner, Sabine Wohlgemuth, Artem Mansurkhodzhaev, Ingrid R Vetter, Marion E Pesenti, Andrea Musacchio.
      Activation of PLK1, a master mitotic kinase, requires phosphorylation of its activation segment on Thr210, within a basic consensus sequence for Aurora kinases. Aurora B-dependent phosphorylation of Thr210 has been reported, but other evidence identified a strict requirement for the Aurora A partner Bora for Thr210 phosphorylation. Here, we investigate the elusive mechanistic basis for this requirement. We show that Aurora A:Bora phosphorylates Thr210 of PLK1 in vitro. On the contrary, T210 was not phosphorylated by isolated Aurora A, additional Aurora A:activator complexes, or Aurora B:INCENP, even when used at high kinase/substrate ratios. A transient interaction of Bora and PLK1, identified by structural modeling and probed mutationally, is uniquely required for Thr210 phosphorylation. Dependency on Bora for Thr210 phosphorylation is eliminated after mutating Lys208, in the Aurora consensus, into arginine. This conservative mutation turns PLK1 into a substrate of nearly all tested active Aurora kinases, including Aurora B. Collectively, these results shine a new light on the specificity of the PLK1 activation mechanism.
    Keywords:  Aurora; Cell Cycle; Kinase; Polo-like Kinase; kinetochore
    DOI:  https://doi.org/10.1038/s44318-025-00681-0
  12. Nat Chem. 2026 Jan 29.
    Biomolecular condensates sustain pH gradients at equilibrium through charge neutralization.
    Hannes Ausserwöger, Rob Scrutton, Charlotte M Fischer, Tomas Sneideris, Daoyuan Qian, Ella de Csilléry, Ieva Baronaite, Kadi L Saar, Alan Z Białek, Marc Oeller, Georg Krainer, Titus M Franzmann, Sina Wittmann, Juan M Iglesias-Artola, Gaetano Invernizzi, Anthony A Hyman, Simon Alberti, Nikolai Lorenzen, Tuomas P J Knowles.
      Electrochemical gradients are essential to the functioning of cells and form across membranes using active transporters. Here we show in contrast that condensed biomolecular systems-often termed condensates-sustain pH gradients without any external energy input. By studying individual condensates on the micrometre scale using a microdroplet platform, we reveal dense-phase pH shifts towards conditions of minimal electrostatic repulsion. We demonstrate that protein condensates can drive substantial alkaline and acidic gradients, which are compositionally tunable and can extend to complex architectures sustaining multiple unique pH conditions simultaneously. Through in silico characterization of human proteomic condensate networks, we further highlight potential wide-ranging electrochemical properties emerging from condensation in nature, while correlating intracellular condensate pH gradients with complex biomolecular composition. Together, the emergent nature of condensation shapes distinct pH microenvironments, thereby creating a regulatory mechanism to modulate biochemical activity in living and artificial systems.
    DOI:  https://doi.org/10.1038/s41557-025-02039-9
  13. Cell. 2026 Jan 27. pii: S0092-8674(25)01485-0. [Epub ahead of print]
    Metabolically regulated proteasome supramolecular organization in situ.
    Xiaomeng Tang, Lu Qu, Florian Wilfling, Florian Beck, Oliver P Ernst, Brenda A Schulman, Wolfgang Baumeister, Cordula Enenkel.
      Many proteins localize in membraneless organelles. However, understanding the steps along membraneless organelle formation-and the structural impact on granule constituents-has been hindered by limited resolution of intracellular data. We address these challenges through in situ cryo-electron tomography (cryo-ET) along with formation of yeast proteasome storage granules (PSGs). During the transition from proliferation to quiescence, doubly capped 26S proteasomes arrested in an inactive state arrange into ∼7.5 MDa trimeric units, dispersed in the nucleoplasm and congregated along the nuclear envelope near the nuclear pore. 9-Å-resolution cryo-ET structures reveal that cytoplasmic PSGs formed in various energy-limiting conditions are paracrystalline arrays of bundled fibers, assembled from stacking of proteasome trimers. The paracrystalline arrangement maintains a pool of fully assembled inactive 26S proteasomes that are released in energy-rich conditions. Overall, our data reveal structural steps along the assembly of an intracellular membraneless organelle in situ and quinary structure formation controlling a major eukaryotic regulatory machine.
    Keywords:  biomolecular condensate; membraneless organelle; metabolism; oligomerization; paracrystalline array; phase separation; proteasome; proteasome storage granule; ubiquitin; yeast
    DOI:  https://doi.org/10.1016/j.cell.2025.12.035
  14. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]
    Lysosomes as hubs of metabolic sensing and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.
    Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
  15. EMBO J. 2026 Jan 26.
    TORC1-dependent translation drives chromatin remodeling during the germ-cell-to-maternal transition in Drosophila.
    Noor M Kotb, Gulay Ulukaya, Anupriya Ramamoorthy, Lina Seojin Park, Julia Tang, Dan Hasson, Prashanth Rangan.
      Proper oogenesis requires a programmed transition from an undifferentiated germ-cell gene expression program to a maternal gene-expression state. While this process depends on the heterochromatin-mediated silencing of germ-cell genes, the upstream mechanisms that enforce this transcriptional shift remain unclear. Here, we uncover a translation-driven chromatin remodeling program that promotes oocyte fate in Drosophila. Through a loss of function screen, we identify TORC1 activity (Mio, Raptor), ribosome biogenesis (Zfrp8, Bystin, Aramis), and a translation factor (eEF1α1) as essential for silencing the germ-cell program. We show that TORC1 activity increases during oocyte specification, and that disruption of TORC1 activity, translation, or ribosome biogenesis during this window impairs heterochromatin maintenance at germ-cell gene loci. Polysome profiling reveals that Zfrp8 promotes translation of the nuclear pore component Nucleoporin 44A (Nup44A), whose function is independently required for chromatin organization and repression of a cohort of germ-cell genes. Taken together, our findings reveal that a transient increase in translation orchestrates chromatin remodeling to ensure commitment to oocyte fate.
    Keywords:  Chromatin; Oocyte; Ribosome; TORC1; Translation
    DOI:  https://doi.org/10.1038/s44318-026-00697-0
  16. Science. 2026 Jan 29. 391(6784): 504-510
    Heritability of intrinsic human life span is about 50% when confounding factors are addressed.
    Ben Shenhar, Glen Pridham, Thaís Lopes De Oliveira, Naveh Raz, Yifan Yang, Joris Deelen, Sara Hägg, Uri Alon.
      How heritable is human life span? If genetic heritability is high, longevity genes can reveal aging mechanisms and inform medicine and public health. However, current estimates of heritability are low-twin studies show heritability of only 20 to 25%, and recent large pedigree studies suggest it is as low as 6%. Here we show that these estimates are confounded by extrinsic mortality-deaths caused by extrinsic factors such as accidents or infections. We use mathematical modeling and analyses of twin cohorts raised together and apart to correct for this factor, revealing that heritability of human life span due to intrinsic mortality is above 50%. Such high heritability is similar to that of most other complex human traits and to life-span heritability in other species.
    DOI:  https://doi.org/10.1126/science.adz1187
  17. Cell. 2026 Jan 28. pii: S0092-8674(25)01487-4. [Epub ahead of print]
    CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis.
    Avi J Samelson, Nabeela Ariqat, Justin McKetney, Gita Rohanitazangi, Celeste Parra Bravo, Rudra S Bose, Kyle J Travaglini, Victor L Lam, Darrin Goodness, Thomas Ta, Gary Dixon, Emily Marzette, Julianne Jin, Ruilin Tian, Eric Tse, Romany Abskharon, Henry S Pan, Emma C Carroll, Rosalie E Lawrence, Jason E Gestwicki, Jessica E Rexach, David S Eisenberg, Nicholas M Kanaan, Daniel R Southworth, John D Gross, Li Gan, Danielle L Swaney, Martin Kampmann.
      Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, dysfunction, and death. However, molecular mechanisms underlying cell-type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPRi screen in induced pluripotent stem cell (iPSC)-derived neurons. The screen uncovered both known and unexpected pathways, including UFMylation and GPI anchor biosynthesis, which control tau oligomer levels. We discovered that the E3 ubiquitin ligase CRL5SOCS4 controls tau levels in human neurons, ubiquitinates tau, and is correlated with resilience to tauopathies in human disease. Disruption of mitochondrial function promotes proteasomal misprocessing of tau, generating disease-relevant tau proteolytic fragments and changing tau aggregation in vitro. These results systematically reveal principles of tau proteostasis in human neurons and suggest potential therapeutic targets for tauopathies.
    Keywords:  CRISPR screen; CUL5; SOCS4; neurodegeneration; protein aggregation; proteostasis; tau
    DOI:  https://doi.org/10.1016/j.cell.2025.12.038
  18. Nat Aging. 2026 Jan 29.
    Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
    Masahiro Wakita, Koyu Ito, Kaho Fujii, Dai Sakamoto, Takumi Mikawa, Sho Sugawara, Xiangyu Zhou, Jeong Hoon Park, Hideka Miyagawa, Daisuke Motooka, Emi Ogasawara, Naotada Ishihara, Akiko Takahashi, Hiroshi Kondoh, Eiji Hara.
      Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.
    DOI:  https://doi.org/10.1038/s43587-025-01057-z
  19. Science. 2026 Jan 29. 391(6784): eadx9445
    DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
    Ines Tomaskovic, Cristian Prieto-Garcia, Maria Boskovic, Mateo Glumac, Tsung-Lin Tsai, Thorsten Mosler, Rubina Kazi, Rajeshwari Rathore, Jorge Andrade, Marina Hoffmann, Giulio Giuliani, Anne-Claire Jacomin, Raquel S Pereira, Elias Knop, Laurens Wachsmuth, Petra Beli, Koraljka Husnjak, Manolis Pasparakis, Andrea Ablasser, Daniela S Krause, Michael Potente, Stamatis Papathanasiou, Janos Terzic, Ivan Dikic.
      DNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes.
    DOI:  https://doi.org/10.1126/science.adx9445
  20. Mol Cell. 2026 Jan 27. pii: S1097-2765(25)01030-5. [Epub ahead of print]
    Ribosome-NAC collaboration: A regulatory platform for cotranslational chaperones, enzymes, and targeting factors.
    Martin Gamerdinger, Nicolas Burg, Elke Deuerling.
      Protein biogenesis requires the ribosome to collaborate with a diverse set of cotranslational factors that shape the fate of nascent chains. These interactions must be precisely choreographed: while cytonuclear proteins require immediate N-terminal maturation and folding, endoplasmic reticulum (ER) and mitochondrial proteins must be maintained in an unfolded state for targeting to their organelles. Reconciling these opposing demands requires a highly selective sorting mechanism operating at the ribosomal exit tunnel. Recent studies identify the conserved nascent polypeptide-associated complex (NAC) as a central coordinator of this process. By sensing nascent signals and dynamically modulating factor access to the ribosome, NAC directs substrates toward the appropriate maturation or targeting pathway. This emerging framework positions NAC as a molecular hub that organizes cotranslational interactions into efficient and orderly protein-biogenesis pathways. In this review, we discuss the mechanistic principles underlying NAC function and consider broader implications for how ribosome-associated networks enforce fidelity in protein biogenesis.
    Keywords:  ER; METAP; MTS; N-acetylation; N-myristoylation; N-myristoyltransferase; N-terminal acetyltransferase; N-terminal modification; NAC; NAT; NMT; NatA; NatD; NatE; SRP; SS; UBA; endoplasmic reticulum targeting; methionine aminopeptidase; methionine excision; mitochondrial targeting sequence; nascent polypeptide-associated complex; ribosome; signal recognition particle; signal sequence; ubiquitin-associated domain
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.031
  21. EMBO J. 2026 Jan 28.
    Molecular basis for the activation of Aurora A and Plk1 kinases during mitotic entry.
    Anaïs Pillan, Philippine Ormancey, Celia Ben Choug, Stephen Orlicky, Nicolas Tavernier, Lucie Van Hove, Batool Ossareh-Nazari, Nicolas Joly, Frank Sicheri, Thierry Lorca, Lionel Pintard.
      The evolutionarily conserved, intrinsically disordered protein Bora is critical for initiating the activation of mitotic kinases. Once phosphorylated at Ser112 by Cyclin A-Cdk1 kinase, phospho-Bora activates unphosphorylated Aurora A kinase (AURKA), directing it towards Polo-like kinase 1 (Plk1), thus promoting Cyclin B-Cdk1 activation and mitotic entry. Here, by combining structural modeling and in vitro assays, we provide evidence that Bora wraps around the N-terminal lobe of AURKA to position its phospho-Ser112 near AURKA's T-loop, mimicking T-loop phosphorylation. Additionally, Bora transiently interacts with the αC helix of the Plk1 kinase domain through a conserved motif, guiding AURKA activity towards the Plk1 T-loop, which is otherwise impervious to phosphorylation by AURKA. We highlight the importance of this motif for Bora function in vitro and during mitotic entry in Xenopus laevis egg extracts. Our results reveal critical molecular details of mitotic kinase activation, which could lead to the development of pathway-specific inhibitors.
    Keywords:  Aurora A; Bora; Cell Division; Mitotic Kinases; Plk1
    DOI:  https://doi.org/10.1038/s44318-025-00679-8
  22. Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01692-4. [Epub ahead of print]45(2): 116920
    Dimerization-dependent gel-like condensation with dsDNA underpins the activation of human cGAS.
    Jacob Lueck, Alexander Strom, Stephanie Martinez Torres, Shuai Wu, Jasper Moh, Hannah Wendorff, Brendan Antiochos, Jungsan Sohn.
      Cyclic G/AMP (cGAMP) synthase (cGAS) initiates inflammatory responses against pathogenic double-stranded (ds)DNA. Although it is well established that cGAS forms phase-separated condensates with dsDNA, its function remains poorly defined. We report here that the dimerization of cGAS on dsDNA creates a mesh-like network, leading to hydrogel-like condensate formation. While cGAS binds to and forms condensates with various nucleic acids, only dsDNA permits the dimerization necessary for activation and gelation. cGAS co-condenses dsDNA and other nucleic acids but retains a distinct dsDNA-mediated gel-like substate that can be dissolved by single-stranded RNA or short dsDNA. Moreover, compared with liquid-like condensates, we find that gel-like condensates are more effective not only in protecting bound dsDNA from exonucleases but also in limiting the mobility of nucleoside triphosphates and the dinucleotide intermediate for cGAMP synthesis. Together, our results show that enzymes can fine-tune surrounding microenvironments to regulate their signaling activities.
    Keywords:  CP: cell biology; CP: immunology; cGAS; condensates; gelation; innate immunity; phase separation; phase transition
    DOI:  https://doi.org/10.1016/j.celrep.2025.116920
  23. Nat Protoc. 2026 Jan 26.
    Putting mammalian early embryonic cells into dormancy.
    Dhanur P Iyer, Heidar Heidari Khoei, Nicolas Rivron, Aydan Bulut-Karslioglu.
      Mammalian development starts at fertilization and continually progresses until birth, except in cases in which an interruption is favorable to the embryo and the mother. Many mammals have the ability to pause development in case of suboptimal resources or routinely as part of their reproductive cycle-a phenomenon called 'embryonic diapause'. Diapause can be mimicked in vivo in mice via surgical removal of the ovaries or hormone injections. This procedure is laborious and invasive, ruling out its use across species. We have developed in vitro protocols through which mouse blastocysts, human blastoids and pluripotent stem cells from both species can be induced to enter a diapause-like dormant state via pharmacological inhibition of mTOR. Here, we describe in detail how embryos, blastoids and stem cells can be transitioned into and out of dormancy under different culture conditions. We further explain critical parameters to ensure success and propose experimental readouts. These in vitro embryonic dormancy setups can be used to uncover molecular mechanisms of dormancy, to test environmental or pharmacological effectors and to further innovate culture systems for species in which in vitro reproductive technologies are limited. We anticipate that researchers with ~1 year of embryo- and stem cell-handling experience should be able to achieve consistent results and evaluate outcomes. Altogether, inducing dormancy in vitro offers the possibility to slow down embryonic development for exploratory investigations of molecular mechanisms and eventually to expand the time window before implantation for clinical assays.
    DOI:  https://doi.org/10.1038/s41596-025-01303-z
  24. Nature. 2026 Jan 28.
    PAF15-PCNA exhaustion governs the strand-specific control of DNA replication.
    Gita Chhetri, Sugith Babu Badugu, Narcis-Adrian Petriman, Mikkel Bo Petersen, Aylin Seren Güller, Nora Fajri, Manon Coulée, Ganesha Pandian Pitchai, Jan Novotný, Frederik Tibert Larsen, Andreas Fønss Møller, Morten Frendø Ebbesen, Tina Ravnsborg, Anoop Kumar Yadav, Barath Balarasa, Anita Lunding, Hana Polasek-Sedlackova, Ole N Jensen, Kim Ravnskjaer, Jonathan R Brewer, Jesper Grud Skat Madsen, Nataliya Petryk, Jens S Andersen, Kumar Somyajit.
      Eukaryotic genome replication is surveyed by the S-phase checkpoint, which coordinates sequential origin activation to prevent the exhaustion of poorly defined, rate-limiting replisome components1-3. Here we show that excessive origin firing saturates chromatin-bound proliferating cell nuclear antigen (PCNA)-a sliding clamp for DNA polymerase processivity and Okazaki fragment processing4-thereby restricting further PCNA loading and lagging-strand synthesis when checkpoint control is lost. PCNA-associated factor 15 (PAF15) emerges as a dosage-sensitive regulator of this process5-9. During unperturbed S phase, the entire soluble PAF15 pool binds to chromatin, leaving no reserve to stabilize PCNA under conditions of excessive origin activation. PAF15 binds to PCNA specifically on the lagging strand through a high-affinity PIP motif and occupies the DNA-encircling channel, protecting the clamp and associated enzymes from premature unloading by the ATAD5-RFC complex. Conversely, overexpression of PAF15 or forced redistribution to the leading strand disrupts replisome progression and induces cell death. These detrimental effects are mitigated by Timeless-Claspin, which blocks PAF15-PCNA binding on the leading strand. E2F4-mediated repression fine-tunes PAF15 expression to ensure optimal dosage and strand specificity. These findings reveal a previously unrecognized replisome constraint: when PAF15-PCNA assemblies are exhausted, the S-phase checkpoint globally restricts origin activation, linking a strand-specific rate-limiting mechanism to global replication dynamics.
    DOI:  https://doi.org/10.1038/s41586-025-10011-3
  25. Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01673-0. [Epub ahead of print]45(2): 116901
    NuMA promotes constitutive heterochromatin compaction by stabilizing linker histone H1 on chromatin.
    Yao Wang, Wenxue Zhao, Jiahao Niu, Cuifang Liu, Xiaotian Wang, Weihong Yuan, Shanshan Ai, Wolfgang Baumeister, Guohong Li, Aibin He, Peng Xu, Cheng Li, Yujie Sun.
      Heterochromatin exerts pivotal functions of silencing specific genes and maintenance of genome stability. However, its formation and maintenance mechanisms remain unclear. Here, we discover that the mitotic regulator NuMA, as a nucleoskeleton protein, is required for constitutive heterochromatin organization at the nucleosome level in interphase. NuMA depletion results in shortened nucleosome repeat length, dispersed nucleosome clutches, increased chromatin accessibility, and disrupted transcription repression of long terminal repeats in heterochromatin regions. Such functions of NuMA rely on its interaction with linker histone H1, which stabilizes H1's binding to chromatin and facilitates nucleosome stacking, as directly visualized by in situ cryo-ET. Notably, NuMA oligomerizes into quasi-meshwork in the nucleoplasm, providing its organization basis as a nucleoskeleton protein. Collectively, our findings illuminate the concerted effect of nucleoskeleton and linker histone on chromatin compaction at the nucleosome level, unveiling a previously unexplored mechanism by which nucleoskeleton regulates heterochromatin formation and maintenance.
    Keywords:  CP: cell biology; CP: molecular biology; NuMA; constitutive heterochromatin; linker histone H1; nucleoskeleton; nucleosome stacking
    DOI:  https://doi.org/10.1016/j.celrep.2025.116901
  26. Nature. 2026 Jan 28.
    GlycoRNA complexed with heparan sulfate regulates VEGF-A signalling.
    Peiyuan Chai, Sina Kheiri, Andrew Kuo, Jessica Shah, Lauren Kageler, Ruiqi Ge, Jonathan Perr, Jennifer Porat, Charlotta G Lebedenko, Joao M L Dias, Eliza Yankova, Sandeep K Rai, Christopher P Watkins, Petar Hristov, Konstantinos Tzelepis, Timothy Hla, Ritu Raman, Eliezer Calo, Jeffrey D Esko, Ryan A Flynn.
      Heparan sulfate proteoglycans (HSPGs) have been recognized as key plasma membrane-tethered co-receptors for a broad range of growth factors and cytokines containing cationic heparan-binding domains1,2. However, how HSPGs mechanistically mediate signalling at the cell surface-particularly in the context of cell surface RNA-remain poorly understood. During developmental and disease processes, vascular endothelial growth factor (VEGF-A), a heparan sulfate-binding factor, regulates endothelial cell growth and angiogenesis3. The regulatory paradigm for endothelial cell-mediated selectively of VEGF-A binding and activity has largely been focused on understanding the selective sulfation of the anionic heparan sulfate chains4-8. Here we examine the organizational rules of a new class of anionic cell surface conjugates, glycoRNAs9,10, and cell surface RNA-binding proteins (csRBPs11,12). Leveraging genome-scale knockout screens, we discovered that heparan sulfate biosynthesis and specifically the 6-O-sulfated forms of heparan sulfate chains are critical for the assembly of clusters of glycoRNAs and csRBPs (cell surface ribonucleoproteins (csRNPs)). Mechanistically, we show that these clusters antagonize heparan sulfate-mediated activation of ERK signalling downstream of VEGF-A. We demonstrate that the heparan sulfate-binding domain of VEGF-A165 is responsible for binding RNA, and that disrupting this interaction enhances ERK signalling and impairs vascular development both in vitro and in vivo and is conserved across species. Our study thus uncovers a previously unrecognized regulatory axis by which csRNPs negatively modulate heparan sulfate-mediated signalling in the context of angiogenesis driven by VEGF-A.
    DOI:  https://doi.org/10.1038/s41586-025-10052-8
  27. Nat Commun. 2026 Jan 28.
    Proteomic profiling of UV damage repair patches uncovers histone chaperones with central functions in chromatin repair.
    Alexandre Plessier, Audrey Chansard, Eliane Petit, Julia Novion Ducassou, Yohann Couté, Sophie E Polo.
      DNA damage compromises not only genome stability but also chromatin integrity, which plays a central role in controlling cell identity. Chromatin repair entails the deposition of new histones at sites of DNA damage. How this is coordinated with parental histone dynamics for the maintenance of chromatin states is unknown. To bridge this knowledge gap, here we devise a novel proteomic strategy to characterize dynamic changes in the chromatin landscape during the repair of UV-induced DNA lesions in human cells, in a quantitative, unbiased and time-resolved manner. Thus, we identify the histone chaperones DNAJC9 and MCM2 as central players in chromatin repair. DNAJC9 provides new H3-H4 histones to CAF-1 and HIRA chaperones for deposition into chromatin and stimulates old H3-H4 histone recovery. MCM2 cooperates with DNAJC9 to coordinate old and new histone dynamics during UV damage repair. Together, our proteomic dataset provides a molecular framework for further dissecting epigenome maintenance mechanisms.
    DOI:  https://doi.org/10.1038/s41467-026-68781-x
  28. Nat Biotechnol. 2026 Jan 27.
    Single-cell proteomic landscape of the developing human brain.
    Tianzhi Wu, Lihua Jiang, Tanzila Mukhtar, Li Wang, Ruiqi Jian, Cheng Wang, Tiffany Trinh, Arnold R Kriegstein, Michael Snyder, Jingjing Li.
      Profiling protein abundance and dynamics at single-cell resolution in complex human tissues is challenging. Given the discordance between transcript and protein abundance observed in studies of the human cerebral cortex, we developed an optimized workflow that combines label-free single-cell mass spectrometry with precise sample preparation to resolve quantitative proteomes of individual cells from the developing human brain. Our method achieves deep proteomic coverage (~800 proteins per cell) even in small immature prenatal human neurons (diameter ~7-10 μm, ~50 pg protein), capturing major brain cell types and enabling proteome-wide characterization at single-cell resolution. We document extensive transcriptome-proteome discordance across cell types, particularly in genes associated with neurodevelopmental disorders. Proteins exhibit markedly higher cell-type specificity than their mRNA counterparts, underscoring the importance of proteomic-level analysis. By reconstructing developmental trajectories from radial glia to excitatory neurons at the proteomic level, we identify dynamic, stage-specific protein co-expression modules and pinpoint the intermediate progenitor-to-neuron transition as a genetically vulnerable phase associated with autism.
    DOI:  https://doi.org/10.1038/s41587-025-02980-7
  29. J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):
    Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
    Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.
      Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.
    DOI:  https://doi.org/10.1083/jcb.202501023
  30. Nature. 2026 Jan 26.
    Scalable and multiplexed recorders of gene regulation dynamics across weeks.
    Lirong Zheng, Dongqing Shi, Yixiao Yan, Bingxin Zhou, Jormay Lim, Yongjie Hou, Bobae An, Jason K Adhinarta, Michael Lin, BumJin Ko, William C Joesten, Mehul Gautam, Elie D M Huez, Eung Chang Kim, Emily G Klyder, Boxuan Chang, Sethuramasundaram Pitchiaya, Michael T Roberts, Denise J Cai, Edward S Boyden, Donglai Wei, Pietro Liò, Changyang Linghu.
      Gene expression is dynamically regulated by gene regulatory networks comprising multiple regulatory components to mediate cellular functions1. An ideal tool for analyzing these processes would track multiple-component dynamics with both spatiotemporal resolution and scalability within the same cells, a capability not yet achieved. Here, we present CytoTape, a genetically encoded, modular protein tape recorder for multiplexed and spatiotemporally scalable recording of gene regulation dynamics continuously for up to three weeks, physiologically compatible, with single-cell, minutes-scale resolution. CytoTape employs a flexible, thread-like, elongating intracellular protein self-assembly engineered via computationally assisted rational design, built on earlier XRI technology2. We demonstrated its utility across multiple mammalian cell types, achieving simultaneous recording of five transcription factor activities and gene transcriptional activities. CytoTape reveals that divergent transcriptional trajectories correlate with transcriptional history and signal integration, and that distinct immediate early genes (IEGs) exhibit complex temporal correlations within single cells. We further extended CytoTape into CytoTape-vivo for scalable, spatiotemporally resolved single-cell recording in the living brain, enabling simultaneous weeks-long recording of doxycycline- and IEG promoter-dependent gene expression histories across up to 14,123 neurons spanning multiple brain regions per mouse. Together, the CytoTape toolkit establishes a versatile platform for scalable and multiplexed analysis of cell physiological processes in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41586-026-10156-9
  31. Science. 2026 Jan 29. 391(6784): 517-521
    Cellular survivorship bias as a mechanistic driver of muscle stem cell aging.
    Jengmin Kang, Daniel I Benjamin, Qiqi Guo, Chauncey Evangelista, Soochi Kim, Marina Arjona, Pieter Both, Mingyu Chung, Ananya K Krishnan, Gurkamal Dhaliwal, Richard Lam, Thomas A Rando.
      Aging is characterized by a decline in the ability of tissue repair and regeneration after injury. In skeletal muscle, this decline is largely driven by impaired function of muscle stem cells (MuSCs) to efficiently contribute to muscle regeneration. We uncovered a cause of this aging-associated dysfunction: a cellular survivorship bias that prioritizes stem cell persistence at the expense of functionality. With age, MuSCs increased expression of a tumor suppressor, N-myc down-regulated gene 1 (NDRG1), which, by suppressing the mammalian target of rapamycin (mTOR) pathway, increased their long-term survival potential but at the cost of their ability to promptly activate and contribute to muscle regeneration. This delayed muscle regeneration with age may result from a trade-off that favors long-term stem cell survival over immediate regenerative capacity.
    DOI:  https://doi.org/10.1126/science.ads9175
  32. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2524367123
    The kinetochore corona orchestrates chromosome congression through transient microtubule interactions.
    Christopher E Miles, Fioranna Renda, Irina Tikhonenko, Angus Alfieri, Alex Mogilner, Alexey Khodjakov.
      For proper segregation of chromosomes and successful cytokinesis, chromosomes must first "congress"-gather in a tight plate near the spindle equator. Molecular mechanism(s) of congression are not fully understood. Here we combine live-cell microscopy, perturbations of microtubule motor activities, correlative light/electron microscopy, and computational modeling, to quantitatively characterize the early-prometaphase movements that bring the scattered chromosomes to the equator in human RPE1 cells. We find that the early-prometaphase movements are directed toward the center of the spindle axis and not the spindle poles. Centromere velocity of the centripetal movements is not constant, with centromeres moving faster at larger distances from the spindle center. We also detect that numerous short microtubules appear at kinetochores at the earliest stages of spindle assembly and prior to chromosome congression. Computational modeling reveals that a mechanism based on brief, stochastic, minus-end directed interactions between the short microtubules protruding from the kinetochores and long appropriately curved microtubules within the spindle accurately predicts the observed distance-velocity function. Further, the model predicts that insufficient numbers of microtubules protruding from the kinetochores decreases the velocity and randomizes directionality of congression movements. These predictions match changes in the chromosome behavior observed in cells with suppressed nucleation of microtubules at the kinetochore corona (RPE1 RodΔ/Δ). In contrast, predictions of computational models based on continuous pulling forces at kinetochores differ significantly from the experimental observations. Together, live-cell observations and modeling reveal a mechanism that enables the efficient and synchronized arrival of chromosomes to the spindle equator.
    Keywords:  chromosomes; computational modeling; mitosis; prometaphase; spindle assembly
    DOI:  https://doi.org/10.1073/pnas.2524367123
  33. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2508686123
    Elucidating chiral myosin-induced actin dynamics: From single-filament behavior to collective structures.
    Takeshi Haraguchi, Kohei Yoshimura, Yasuhiro Inoue, Takuma Imi, Koyo Hasegawa, Taisei Nagai, Hideki Furusawa, Toshifumi Mori, Kenji Matsuno, Kohji Ito.
      The myosin superfamily encompasses over 70 classes, each with multiple subclasses, and exhibits substantial diversity in properties such as velocity, ATPase activity, duty ratio, and directionality. This functional diversity enables the specialized roles of each myosin in various organisms, organs, and cell types. Beyond these well-characterized parameters, a newly recognized property has recently come into focus: Certain myosins drive actin filaments along chiral curved trajectories. However, this newly identified property remains largely unexplored. Here, we investigated this chiral motion in vitro using Chara corallina myosin XI (CcXI), which drives fast clockwise (CW) movement of actin filaments. This chiral motion arises from asymmetric displacement at the filament's leading tip, and its curvature depends on the myosin density. Surprisingly, at elevated actin concentrations, filaments exhibiting chiral curved motion undergo collective dynamics, spontaneously forming a ring-shaped structure-termed the actin chiral ring (ACR)-that exhibits persistent CW rotation. ACRs display remarkable stability, continuing to rotate at their formation site until ATP is depleted, while maintaining their structure even after rotation ceases. This stability has not been reported among reported collective motions of cytoskeletal proteins driven by various motors. Our findings demonstrate that myosins with chiral activity can autonomously organize actin filaments into stable, chiral structures through collective motion, providing insights into actin self-organization by unconventional myosins. This paradigm offers a mechanistic basis for how motor-driven molecular asymmetry can give rise to coherent structural chirality at the cellular scale-an essential step in the emergence of cell chirality and asymmetry during development.
    Keywords:  actin; chirality; collective motion; myosin; self-assembly
    DOI:  https://doi.org/10.1073/pnas.2508686123
  34. Elife. 2026 Jan 26. pii: RP95576. [Epub ahead of print]13
    Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
    Kanako Shinno, Yuri Miura, Koichi M Iijima, Emiko Suzuki, Kanae Ando.
      Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.
    Keywords:  D. melanogaster; aging; autophagy; cell biology; mitochondria; neuronal proteostasis; protein aggregation; proteome
    DOI:  https://doi.org/10.7554/eLife.95576
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