bims-ginsta 2025-08-31 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2025–08–31
forty-two papers selected by
Jinrong Hu, National University of Singapore

Mechanical confinement governs phenotypic plasticity in melanoma.
Ovarian germline stem cell dedifferentiation is cytoneme dependent.
Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.
Compressive stress drives morphogenetic apoptosis through lateral tension and Piezo.
Kif11-haploinsufficient oocytes reveal spatially differential requirements for chromosome biorientation.
Conversion of natural cytokine receptors into orthogonal synthetic biosensors.
A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.
Thymic epithelial cells amplify epigenetic noise to promote immune tolerance.
α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.
NAC couples protein synthesis with nascent polypeptide myristoylation on the ribosome.
Transient gene melting governs the timing of oligodendrocyte maturation.
Supracellular actomyosin assemblies: master coordinators of development.
Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors.
Mechanisms of transmembrane domain recognition during endoplasmic reticulum quality control.
NSUN2 facilitates DICER cleavage of DNA damage-associated R-loops to promote repair.
Endocardial primary cilia and blood flow regulate EndoMT during endocardial cushion development.
LYVAC/PDZD8 is a lysosomal vacuolator.
SKP1A bound to Polycomb-silenced genes mediates degradation of PRC2 and preconditions their activation.
Dual mitotic bookmarking by GAF and H3K27ac orchestrates differential propagation of cell fate memory in neural development.
Endocytosis is essential for cysteine-deprivation-induced ferroptosis.
Quantitative imaging of lipid transport in mammalian cells.
Corrections in single-cell migration path in vivo are controlled by pulses in polar Rac1 activation.
Oxidative stress response protein delays ovarian aging by promoting stress granule clearance.
Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress.
Migrating mesoderm cells self-organize into a dynamic meshwork structure during chick gastrulation.
Oncometabolite 5-IP7 inhibits inositol 5-phosphatase to license E-cadherin endocytosis.
Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation.
The cAMP-PKA signaling initiates mitosis by phosphorylating Bora.
Cells prioritize the regulation of cell mass density.
Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation.
Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength.
Mevalonate metabolites boost aged oocyte quality through prenylation of small GTPases.
A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response.
Efficient termination of transcription by RNA polymerase I requires a conserved hairpin of the ribosomal RNA precursor.
Early lineage segregation of primary myotubes from secondary myotubes and adult muscle stem cells.
Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism.
CHIP protects lysosomes from CLN4 mutant-induced membrane damage.
Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.
Epsin1 enforces a condensation-dependent checkpoint for ubiquitylated cargo during clathrin-mediated endocytosis.
DNA double-strand break end resection factors and WRN facilitate mitotic DNA synthesis in human cells.
A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy.
High-Resolution Spatial Transcriptomics Unveils Spatially Resolved Gene Modules and Fatty Acid Metabolism Dysregulation in Human Skin Aging.

Nature. 2025 Aug 27.

Mechanical confinement governs phenotypic plasticity in melanoma.

Miranda V Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P Koche, Richard M White.

Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.

DOI: https://doi.org/10.1038/s41586-025-09445-6
Proc Natl Acad Sci U S A. 2025 Sep 02. 122(35): e2426145122

Ovarian germline stem cell dedifferentiation is cytoneme dependent.

Catherine Sutcliffe, Nabarun Nandy, Raluca Revici, Heather Johnson, Shukry J Habib, Hilary L Ashe, Scott G Wilcockson.

  Progenitor cell dedifferentiation is important for stem cell maintenance during tissue repair and age-related stem cell decline. Here, we use the Drosophila ovary as a model to study the role of cytonemes in bone morphogenic protein (BMP) signaling-directed germline stem cell (GSC) maintenance and dedifferentiation of germ cells to GSCs. We provide evidence that differentiating germ cell cysts extend longer cytonemes that are more polarized toward the niche during dedifferentiation to reactivate BMP signaling. The presence of additional somatic cells in the niche is associated with a failure of germ cell dedifferentiation, consistent with the formation of a physical barrier to cytoneme-niche contact and outcompetition of germ cells for BMP. Using BMP beads in vitro, we show that these are sufficient to induce cytoneme-dependent contacts in Drosophila tissue culture cells. We demonstrate that the Enabled (Ena) actin polymerase is localized to the tips of germ cell cytonemes and is necessary for robust cytoneme formation, as its mislocalization reduces the frequency, length, and directionality of cytonemes. During homeostasis, specifically perturbing cytoneme function through Ena mislocalization impairs GSC fitness by reducing GSC BMP signaling and niche occupancy. Disrupting cytonemes by targeting Ena during dedifferentiation reduces germ cell BMP responsiveness and the ability of differentiating cysts to dedifferentiate. Overall, our results provide evidence that cytonemes play a fundamental role in establishing polarized signaling and niche occupancy during stem cell maintenance and dedifferentiation.

Keywords:  BMP signaling; cytoneme; dedifferentiation; enabled; germline stem cell

DOI:  https://doi.org/10.1073/pnas.2426145122
Dev Cell. 2025 Aug 13. pii: S1534-5807(25)00496-4. [Epub ahead of print]

Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.

Ly-Sha Ee, Daniel Medina-Cano, Emily Goetzler, Christopher Uyehara, Clayton Schwarz, Eralda Salataj, Subhashini Madhuranath, Todd Evans, Anna-Katerina Hadjantonakis, Effie Apostolou, Alexander Polyzos, Thomas Vierbuchen, Matthias Stadtfeld.

  The molecular mechanisms that drive essential patterning events in the mammalian embryo remain poorly understood. Analysis of transcription factor expression kinetics at peri-gastrulation stages of development suggest Otx2 as a candidate regulator of the definitive endoderm, the precursor of all gut-derived organs. Accordingly, timed OTX2 depletion in gastruloids or during directed differentiation results in abnormal definitive endoderm specification in mouse and human, characterized by altered expression of components and transcriptional targets of the canonical WNT signaling pathway, perturbed adhesion and migration programs, and de-repression of regulators of other lineages. These defects cumulate in impaired foregut formation. Mechanistically, OTX2 is required to activate a subset of endoderm-specific enhancers and to suppress select enhancers of other lineages, allowing timely exit from the primitive streak and correct specification of anterior endoderm. Our results establish OTX2 as an early gut regulator and suggest molecular principles underlying spatiotemporal cell identity conserved across germ layers and species.

Keywords:  H3K27ac; OTX2; anterior-posterior; definitive endoderm; enhancers; foregut; gastrulation; germ layer specification; patterning; transcription factor

DOI:  https://doi.org/10.1016/j.devcel.2025.07.020
Cell Rep. 2025 Aug 19. pii: S2211-1247(25)00932-5. [Epub ahead of print]44(9): 116161

Compressive stress drives morphogenetic apoptosis through lateral tension and Piezo.

Tatiana Merle, Martine Cazales, Thomas Mangeat, Ronan Bouzignac, Amsha Proag, Brice Ronsin, Christian Rouvière, Eve Pitot, Magali Suzanne.

  Tissues and organs constantly experience physical stress, including compression. Although the impact of overcrowding-induced compression on cell extrusion has been studied, its role in morphogenesis remains largely unexplored. Here, we show that natural compression exerted by the surrounding envelope on the developing Drosophila leg is required for proper morphogenesis. In this tissue, apoptosis, enriched in the future fold region, contributes to tissue folding by generating apical pulling forces. Yet only a subset of cells within the proapoptotic domain die, and how this pattern emerges was unknown. We found that natural compression regulates apoptosis, revealing compression as an integral part of its control during leg morphogenesis. Compression increases lateral cell tension and promotes apoptosis via the mechanosensor Piezo. Finally, interfering with cell cortex anchoring blocks this process. Altogether, our results indicate that compressive stress is actively integrated into the developmental program, driving both apoptosis and tissue folding.

Keywords:  CP: Cell biology; Drosophila; Piezo; apoptosis; compressive stress; membrane tension; morphogenesis

DOI:  https://doi.org/10.1016/j.celrep.2025.116161
EMBO Rep. 2025 Aug 20.

Kif11-haploinsufficient oocytes reveal spatially differential requirements for chromosome biorientation.

Tappei Mishina, Aurélien Courtois, Shuhei Yoshida, Kohei Asai, Hiroshi Kiyonari, Tomoya S Kitajima.

  Bipolar spindle assembly and chromosome biorientation are prerequisites for chromosome segregation during cell division. The kinesin motor KIF11 (also widely known as Eg5) drives spindle bipolarization by sliding antiparallel microtubules bidirectionally, elongating a spherical spindle into a bipolar-shaped structure in acentrosomal oocytes. During meiosis I, this process stretches homologous chromosome pairs, establishing chromosome biorientation at the spindle equator. The quantitative requirement for KIF11 in acentrosomal spindle bipolarization and homologous chromosome biorientation remains unclear. Here, using a genetic strategy to modulate KIF11 expression levels, we show that Kif11 haploinsufficiency impairs spindle elongation, leading to the formation of a partially bipolarized spindle during meiosis I in mouse oocytes. While the partially bipolarized spindle allows chromosome stretching in the inner region of its equator, it fails to do so in the outer region, where merotelic kinetochore-microtubule attachments are favored to form. These findings demonstrate the necessity of biallelic functional Kif11 for bipolar spindle assembly in acentrosomal oocytes and reveal a spatially differential requirement for homologous chromosome biorientation within the spindle.

Keywords:  Chromosome Segregation; Meiosis; Oocyte; Spindle

DOI:  https://doi.org/10.1038/s44319-025-00539-w
Nat Chem Biol. 2025 Aug 22.

Conversion of natural cytokine receptors into orthogonal synthetic biosensors.

Hailey I Edelstein, Amparo Cosio, Max L Ezekiel, William K Corcoran, Aaron H Morris, Joshua N Leonard.

Synthetic receptors enable bioengineers to build cell-based therapies that perform therapeutic functions in a targeted or conditional fashion to enhance specificity and efficacy. Although many synthetic receptors exist, it remains challenging to generate new receptors that sense soluble cues and relay that detection through orthogonal mechanisms independent of native pathways. Here we co-opt natural cytokine receptor ectodomains into modular extracellular sensor architecture (MESA) receptors to form natural ectodomain (NatE) MESA receptors. We generated multiple functional, orthogonal synthetic cytokine receptors, identified design principles and constraints and propose guidance for extending this approach to other natural receptors. We demonstrate the utility of NatE MESA by engineering T cells to sense an immunosuppressive cue and respond with customized transcriptional output to support chimeric antigen receptor T cell activity. Lastly, we multiplex NatE MESA to logically evaluate multiple cues associated with the tumor microenvironment. These technologies and learnings will enable engineering cellular functions for new applications.

DOI: https://doi.org/10.1038/s41589-025-01986-1
Mol Cell. 2025 Aug 21. pii: S1097-2765(25)00646-X. [Epub ahead of print]

A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.

Julia Vorhauser, Theodoros I Roumeliotis, David Coupe, Jacky K Leung, Lu Yu, Kristin Böhlig, Thomas Zerjatke, Ingmar Glauche, André Nadler, Jyoti S Choudhary, Jörg Mansfeld.

  Reactive oxygen species (ROS) influence cell proliferation and fate decisions by oxidizing cysteine residues (S-sulfenylation) of proteins, but specific targets and underlying regulatory mechanisms remain poorly defined. Here, we employ redox proteomics to identify cell-cycle-coordinated S-sulfenylation events and investigate their functional role in proliferation control. Although ROS levels rise during cell cycle progression, the overall oxidation of the proteome remains constant, with dynamic S-sulfenylation restricted to a subset of cysteines. Among these, we identify a critical redox-sensitive cysteine residue (C41) in the cyclin-dependent kinase (CDK) inhibitor p21. C41 oxidation regulates the interaction of p21 with CDK2 and CDK4, controlling a double-negative feedback loop that determines p21 stability. When C41 remains reduced, p21's half-life increases in the G2 phase, resulting in more p21 inheritance to daughter cells, suppressing proliferation and promoting senescence after irradiation. Notably, we identify dynamic S-sulfenylation on further cell cycle regulators, implying coordination of cell cycle and redox control.

Keywords:  CDKN1A; Cdk2; Cdk4; G2 phase; ROS; S-sulfenylation; cell cycle; cell cycle exit; decision-making; negative feedback loop; oxidation; p21; proliferation; reactive oxygen species; redox; redox proteomics; redox switch; reduction; senescence; sulfenic acid

DOI:  https://doi.org/10.1016/j.molcel.2025.07.023
Nature. 2025 Aug 20.

Thymic epithelial cells amplify epigenetic noise to promote immune tolerance.

Noah Gamble, Jason A Caldwell, Joshua McKeever, Caroline Kaiser, Alexandra Bradu, Peyton J Dooley, Sandy Klemm, William J Greenleaf, Narutoshi Hibino, Aaron R Dinner, Andrew S Koh.

Cellular plasticity is a principal feature of vertebrate adaptation, tissue repair and tumorigenesis1,2. However, the mechanisms that regulate the stability of somatic cell fates remain unclear. Here, we use the somatic plasticity of thymic epithelial cells, which facilitates the selection of a self-discriminating T cell repertoire3, as a physiological model system to show that fluctuations in background chromatin accessibility in nucleosome-dense regions are amplified during thymic epithelial maturation for the ectopic expression of genes restricted to other specialized cell types. This chromatin destabilization was not dependent on AIRE-induced transcription but was preceded by repression of the tumour suppressor p53. Augmenting p53 activity indirectly stabilized chromatin, inhibited ectopic transcription, limited cellular plasticity and caused multi-organ autoimmunity. Genomic regions with heightened chromatin accessibility noise were selectively enriched for nucleosome-destabilizing polymeric AT tracts and were associated with elevated baseline DNA damage and transcriptional initiation. Taken together, our findings define molecular levers that modulate cell fate integrity and are used by thymic epithelial cells for immunological tolerance.

DOI: https://doi.org/10.1038/s41586-025-09424-x
Nat Chem Biol. 2025 Aug 22.

α-Ketoglutarate dictates AMPK protein synthesis for energy sensing in human cancers.

Wen Mi, Yun Xue, Haohang Yan, Yurou Zhang, Xinlei Cai, Shuyuan Zhang, Ruiping He, Liucheng Li, Lingzhi Zhu, Xinyi Xia, Yifan Liang, Chongwen Cao, Yi Xu, Junfeng Bi, Guanlin Wang, Li Chen, Dan Ye, Fei Li, Ruobing Ren, Pingyu Liu, Hongbin Ji, Fuming Li.

The energy sensor AMP-activated protein kinase (AMPK) promotes tumor cell survival under stress but how to prevent AMPK activation to blunt tumor progression remains unclear. Here we show that the metabolite α-ketoglutarate (α-KG) dictates AMPK translation through a TET-YBX1 axis, which can be exploited to sensitize human cancer cells to energy stress. α-KG-deficient cells fail to activate AMPK under glucose starvation, which elicits cytosolic NADPH depletion and disulfidptosis. Mechanistically, α-KG insufficiency inhibits TET-dependent transcription of YBX1, an RNA-binding protein required for human-specific AMPK protein synthesis. Similarly, α-KG competitors including succinate and itaconate inhibit the YBX1-AMPK axis and sensitize cancer cells to glucose deprivation. Lastly, cotargeting oncogenic YBX1 and GLUT1 creates synthetic lethality and blunts tumor growth in vivo. Together, our findings link α-KG to energy sensing through AMPK translation and propose that targeting α-KG-YBX1-dependent AMPK translation can sensitize human cancer cells to energy stress for treatment.

DOI: https://doi.org/10.1038/s41589-025-02013-z
EMBO J. 2025 Aug 26.

NAC couples protein synthesis with nascent polypeptide myristoylation on the ribosome.

Sara Zdancewicz, Emir Maldosevic, Kinga Malezyna, Ahmad Jomaa.

  N-glycine myristoylation allows for reversible association of newly synthesized proteins with membranes to regulate essential functions such as cellular signaling and stress responses. This process can be catalyzed during protein synthesis by N-myristoyltransferases (NMTs), and its dysregulation has been implicated both in cancer and heart disease. Although the nascent polypeptide-associated complex (NAC) orchestrates the binding of several co-translational processing factors on ribosomes, its role in facilitating nascent protein myristoylation by NMT2 remains unclear. Here, we show that NAC mediates binding of NMT2 to translating ribosomes, which together form an extended channel that guides the nascent chain as it emerges from the polypeptide exit tunnel to the catalytic site of NMT2. Furthermore, the ternary ribosome:NMT2:NAC complex is stabilized by a ribosomal RNA clamp that, together with NAC, orients NMT2 on the ribosomal surface for co-translational myristoylation of nascent chains. Our work uncovers the molecular mechanism coupling protein synthesis to nascent protein myristoylation and underscores the role of NAC as a master regulator of protein biogenesis on the ribosome.

Keywords:  Cryo-EM; N-myristoyltransferases; NAC; NMT2; Nascent Chain; Translating Ribosome

DOI:  https://doi.org/10.1038/s44318-025-00548-4
Cell. 2025 Aug 19. pii: S0092-8674(25)00861-X. [Epub ahead of print]

Transient gene melting governs the timing of oligodendrocyte maturation.

Kevin C Allan, Jesse J Zhan, Andrew R Morton, Erin F Cohn, Marissa A Scavuzzo, Anushka Nikhil, Matthew S Elitt, Benjamin L L Clayton, Lucille R Hu, H Elizabeth Shick, Jost K Vrabic, Hannah E Olsen, Daniel C Factor, Jonathan E Henninger, Gemma Bachmann, Berit E Powers, Richard A Young, Charles Y Lin, Peter C Scacheri, Tyler E Miller, Paul J Tesar.

  Cellular maturation is a crucial step for tissue formation and function, distinct from the initial steps of differentiation and cell fate specification. In the central nervous system, failure of oligodendrocyte maturation is linked to diseases such as multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After progenitor cells differentiate into immature oligodendrocytes, the transcription factor SOX6 redistributes from super-enhancers to cluster across specific gene bodies. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turn off upon maturation. Suppression of SOX6 deactivates these immaturity loci, accelerating the transition to mature, myelinating oligodendrocytes. Notably, cells harboring this immature SOX6 gene signature are enriched in multiple sclerosis patient brains and antisense oligonucleotide-mediated Sox6 knockdown drives oligodendrocyte maturation in mice. Our findings establish SOX6 as a key regulator of oligodendrocyte maturation and highlight its potential as a therapeutic target to promote myelination in disease.

Keywords:  Sox6; development; differentiation; epigenetic; maturation; multiple sclerosis; myelin; oligodendrocyte

DOI:  https://doi.org/10.1016/j.cell.2025.07.039
Development. 2025 Aug 15. pii: dev204896. [Epub ahead of print]152(16):

Supracellular actomyosin assemblies: master coordinators of development.

Katja Röper.

  Most movement in biological systems is driven by assemblies of actomyosin, be it in the form of sarcomeres in muscles or as actomyosin networks in non-muscle cells. Actomyosin has several key functions within epithelial cells, the cells that will form most of the organs of an animal during development. One such function is to support cellular shape through an actomyosin cortex just underneath the plasma membrane. In addition, actomyosin accumulates apically at adherens and tight junctions, supporting cell-cell adhesion and epithelial tightness. Evidence over recent years has shown that apical actomyosin can also organise into 'supracellular' networks that seemingly span many cells. These large-scale assemblies either form interlinked networks of apical-medial actomyosin just underneath the free apical plasma membrane or form linear actomyosin cables at the level of adherens junctions. Both types of supracellular assemblies appear to be conserved across evolution, though were characterised in Drosophila. In this Review, I discuss the formation of these supracellular structures, the tissues in which they are known to function during development, their functional roles, and the remaining unknowns regarding their components and potential emergent properties.

Keywords:  Actomyosin; Cable; Epithelial cells; Morphogenesis; Supracellular

DOI:  https://doi.org/10.1242/dev.204896
Nature. 2025 Aug 20.

Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors.

Shilpa Singh, Catherine E Gleason, Min Fang, Yasmin N Laimon, Vishal Khivansara, Shanhai Xie, Yavuz T Durmaz, Aniruddha Sarkar, Kenneth Ngo, Varunika Savla, Yixiang Li, Muhannad Abu-Remaileh, Xinyue Li, Marie-Anais Locquet, Bishma Tuladhar, Ranya Odeh, Frances Hamkins-Indik, Daphne He, Miles W Membreno, Meisam Nosrati, Nathan N Gushwa, Siegfried S F Leung, Breena Fraga-Walton, Luis Hernandez, Miguel P Baldomero, Bryan M Lent, David Spellmeyer, Joshua F Luna, Dalena Hoang, Yuliana Gritsenko, Manesh Chand, Megan K DeMart, Sammy Metobo, Chinmay Bhatt, Justin A Shapiro, Kai Yang, Nathan J Dupper, Andrew T Bockus, Jinshu Fang, Ramesh Bambal, Peadar Cremin, John G Doench, James B Aggen, Li-Fen Liu, Bernard Levin, Evelyn W Wang, Iolanda Vendrell, Roman Fischer, Benedikt Kessler, Prafulla C Gokhale, Sabina Signoretti, Alexander Spektor, Constantine Kreatsoulas, Marie Evangelista, Rajinder Singh, David J Earp, Deepak Nijhawan, Pablo D Garcia, Matthew G Oser.

Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1-S checkpoint and leading to dysregulated E2F activity1. Other cancers similarly disrupt the G1-S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity2,3. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis4-9, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs10-13. Cyclin A represses E2F through an RxL-dependent interaction10,14, which, when disrupted, hyperactivates E2F15. However, this substrate interface has remained difficult to target. Here we developed cell-permeable, orally bioavailable macrocyclic peptides that inhibit RxL-mediated interactions of cyclins with their substrates. Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A-E2F and cyclin B-MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B-CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers.

DOI: https://doi.org/10.1038/s41586-025-09433-w
Curr Opin Cell Biol. 2025 Aug 22. pii: S0955-0674(25)00118-8. [Epub ahead of print]96 102580

Mechanisms of transmembrane domain recognition during endoplasmic reticulum quality control.

Nikita Sergejevs, Pedro Carvalho.

Misfolded proteins can be toxic to cells, and their accumulation is a hallmark of diseases such as neurodegeneration. Normally, protein homeostasis is maintained by quality control processes that eliminate misfolded proteins. In the endoplasmic reticulum (ER), misfolded proteins are eliminated through endoplasmic reticulum-associated degradation (ERAD). This process is mediated by ubiquitin ligase complexes that recognize substrates in the membrane and lumen of the ER and retrotranslocate them to the cytosol to mediate their ubiquitination for subsequent degradation by the proteasome. While the recognition of luminal substrates is well understood, how ERAD complexes specifically identify and select aberrant membrane proteins remains poorly defined. Here, we review examples of intramembrane substrate recognition during ERAD and discuss the principles involved.

DOI: https://doi.org/10.1016/j.ceb.2025.102580
Nat Commun. 2025 Aug 23. 16(1): 7882

NSUN2 facilitates DICER cleavage of DNA damage-associated R-loops to promote repair.

Adele Alagia, Kamal Ajit, Arianna Di Fazio, Qilin Long, Monika Gullerova.

DNA integrity is constantly challenged by both endogenous and exogenous damaging agents, resulting in various forms of damage. Failure to repair DNA accurately leads to genomic instability, a hallmark of cancer. Distinct pathways exist to repair different types of DNA damage. Double-strand breaks (DSBs) represent a particularly severe form of damage, due to the physical separation of DNA strands. The repair of DSBs requires the activity of RNA Polymerase II (RNAPII) and the generation of Damage-responsive transcripts (DARTs). Here we show that the RNA m5C-methyltransferase NSUN2 localises to DSBs in a transcription-dependent manner, where it binds to and methylates DARTs. The depletion of NSUN2 results in an accumulation of nascent primary DARTs around DSBs. Furthermore, we detect an RNA-dependent interaction between NSUN2 and DICER, which is stimulated by DNA damage. NSUN2 activity promotes DICER cleavage of DARTs-associated R-loops, which is required for efficient DNA repair. We report a role of the RNA m5C -methyltransferase NSUN2 within the RNA-dependent DNA damage response, highlighting its function as a DICER chaperone for the clearance of non-canonical substrates such as DARTs, thereby contributing to genomic integrity.

DOI: https://doi.org/10.1038/s41467-025-63220-9
Nat Cardiovasc Res. 2025 Aug 26.

Endocardial primary cilia and blood flow regulate EndoMT during endocardial cushion development.

Kathryn Berg, Joshua Gorham, Faith Lundt, Jonathan Seidman, Martina Brueckner.

Valvular heart disease affects 2.5% of the population and is frequently associated with congenital heart disease. Blood flow is critical for valve formation, but the cellular mechanosensors translating flow into the transcriptional regulation of valve development remain undiscovered. Here, we identify that primary cilia and blood flow in mouse embryos regulate early valve development in vivo by regionally controlling endothelial-to-mesenchymal transition (EndoMT) through the modulation of Krüppel-like factor 4 (Klf4) in the endocardial cushions. Endocardial ciliation decreases during cushion development in regions of high shear stress, correlating with KLF4 downregulation and EndoMT progression. Mouse embryos lacking cilia exhibit blood flow-dependent accumulation of KLF4 and impaired cushion cellularization. Single-nucleus RNA sequencing revealed that the cilia-knockout and contractility-knockout endocardium fails to progress through EndoMT pseudostages, retains endothelial markers, and has reduced EndoMT and mesenchymal genes that KLF4 antagonizes. These data indicate that endocardial primary cilia function as mechanosensors in cushion development through the regional regulation of KLF4.

DOI: https://doi.org/10.1038/s44161-025-00697-z
Science. 2025 Aug 21. 389(6762): eadz0972

LYVAC/PDZD8 is a lysosomal vacuolator.

Haoxiang Yang, Jinrui Xun, Yajuan Li, Awishi Mondal, Bo Lv, Simon C Watkins, Lingyan Shi, Jay Xiaojun Tan.

Lysosomal vacuolation is commonly found in many pathophysiological conditions, but its molecular mechanisms and functions remain largely unknown. Here, we show that the endoplasmic reticulum (ER)-anchored lipid transfer protein PDZ domain-containing 8 (PDZD8), which we propose to be renamed as lysosomal vacuolator (LYVAC), is a general mediator of lysosomal vacuolation. Using human cell lines, we found that diverse lysosomal vacuolation inducers converged on lysosomal osmotic stress, triggering LYVAC recruitment through multivalent interactions. Stress-induced lysosomal lipid signaling contributed to both the recruitment and activation of LYVAC. By directly sensing lysosomal phosphatidylserine and cholesterol, the lipid transfer domain of LYVAC mediated directional ER-to-lysosome lipid movement, leading to osmotic membrane expansion of lysosomes. These findings uncover an essential mechanism for lysosomal vacuolation with broad implications in pathophysiology.

DOI: https://doi.org/10.1126/science.adz0972
Mol Cell. 2025 Aug 20. pii: S1097-2765(25)00654-9. [Epub ahead of print]

SKP1A bound to Polycomb-silenced genes mediates degradation of PRC2 and preconditions their activation.

Takashi Kondo, Shinsuke Ito, Junichiro Takano, Yong-Woon Han, Takaho Endo, Kaori Kondo, Marika Shibata, Yusuke Kawashima, Hiroki Sugishita, Mio Harachi, Jafar Sharif, Jun Seita, Osamu Ohara, Manabu Nakayama, Haruhiko Koseki.

  Polycomb group (PcG) proteins are repressors of developmental genes. Paradoxically, the same PcG proteins also function in gene activation via mechanisms that are not yet fully understood. Here, we found that SKP1A, an essential factor of SKP1A/CUL1/F-box (SCF) ubiquitin ligases and Polycomb-repressive complex 1 (PRC1) containing PCGF1 (PCGF1-PRC1), mediates the link between PcG-dependent gene regulation and ubiquitin proteasomal degradation. By using differentiating mouse embryonic stem cells and the midbrain of developing mouse embryos, we found that SKP1A removes EED, a core component of PRC2 that is bound to PcG-target-gene promoters, via proteasomal degradation, and it thereby sensitizes these genes for subsequent activation. In summary, we reveal here a previously unknown role of SKP1A in preconditioning activation of PcG-target genes via the proteasomal degradation of PRC2. This indicates that SKP1A-containing PCGF1-PRC1 may contribute to confer reversibility on PcG-mediated gene silencing for spatiotemporal regulation of target genes.

Keywords:  PRC1; PRC2; Polycomb; gene regulation; proteasome; ubiquitination

DOI:  https://doi.org/10.1016/j.molcel.2025.08.004
Nat Commun. 2025 Aug 25. 16(1): 7930

Dual mitotic bookmarking by GAF and H3K27ac orchestrates differential propagation of cell fate memory in neural development.

Rulan Zhang, Jie Liu, Zimo Zhang, Zili Chen, Tanpeng Wang, Yuying Shen, Zejun Lan, Jingyi Chu, Haoxuan Tang, Xiyue Zhang, Yan Song.

In brain development, neural stem cells (NSCs) undergo asymmetric cell divisions to replicate themselves and meanwhile produce differentiating siblings. It remains obscure how NSCs preserve their self-renewing fate across mitosis. Even less is known how cell fate memory is differentially propagated to sibling daughter cells adopting distinct cell fates. Here we found that key differentiation genes are dually bookmarked by pioneer factor GAF (GAGA factor) and H3K27ac in asymmetrically-dividing Drosophila central brain NSCs. In daughter cells adopting NSC fate, GAF promotes self-renewal through timely inhibiting differentiation genes via HDAC1-mediated H3K27 deacetylation, whereas in sibling daughter cells adopting neural progenitor fate, GAF occupancy is replaced by competitor SWI/SNF complex, allowing retention of H3K27ac mark and fast activation of differentiation genes. Thus, our study unveils a paradigm by which cell fate memory can be differentially transmitted to sibling daughter cells via dual antagonistic mitotic bookmarking and selective molecular competition mechanism.

DOI: https://doi.org/10.1038/s41467-025-62974-6
Mol Cell. 2025 Aug 19. pii: S1097-2765(25)00656-2. [Epub ahead of print]

Endocytosis is essential for cysteine-deprivation-induced ferroptosis.

Xuesong Liu, Zechuan Zhao, Zhixuan Bian, Fahad A Benthani, Yingying Hu, Deguang Liang, Xuejun Jiang.

  Ferroptosis is a form of cell death caused by iron-dependent phospholipid peroxidation and subsequent membrane rupture. Autophagic degradation of the iron-storage protein ferritin promotes ferroptosis by increasing cytosolic bioactive iron, presumably explaining how lysosomal inhibitors suppress ferroptosis. Surprisingly, we found that lysosomal inhibitors suppress cysteine-deprivation-induced (CDI) ferroptosis, even in autophagy-defective cells, and subsequently discovered that clathrin-mediated endocytosis (CME) of transferrin is essential for CDI ferroptosis. Blocking lysosomal proteolytic activity failed to inhibit ferroptosis, whereas disrupting endosomal acidification and eliminating the endocytic protein AP2M1 both impeded ferroptosis. Conversely, replenishing cellular iron with ferric ammonium citrate, but not with transferrin, restored CDI ferroptosis in endocytosis-deficient cells. Unexpectedly, abolishing endosomal acidification, CME, and the associated increase in cellular labile iron could not prevent ferroptosis triggered by direct inhibition of the ferroptosis-suppressing enzyme glutathione peroxidase-4 (GPX4). Together, this study reveals the essential role of endocytosis, specifically for CDI ferroptosis.

Keywords:  AP2M1; GPX4; autophagy; cysteine deprivation; endocytosis; endosome; ferroptosis; iron; lysosome; transferrin

DOI:  https://doi.org/10.1016/j.molcel.2025.08.006
Nature. 2025 Aug 20.

Quantitative imaging of lipid transport in mammalian cells.

Juan M Iglesias-Artola, Kristin Böhlig, Kai Schuhmann, Katelyn C Cook, H Mathilda Lennartz, Milena Schuhmacher, Pavel Barahtjan, Cristina Jiménez López, Radek Šachl, Vannuruswamy Garikapati, Karina Pombo-Garcia, Annett Lohmann, Petra Riegerová, Martin Hof, Björn Drobot, Andrej Shevchenko, Alf Honigmann, André Nadler.

Eukaryotic cells produce over 1,000 different lipid species that tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unclear, owing to the difficulty of imaging lipid transport in cells3. Here we measured the retrograde transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high-resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting, in contrast to the slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between energy-dependent lipid flipping and non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids, while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.

DOI: https://doi.org/10.1038/s41586-025-09432-x
Curr Biol. 2025 Aug 18. pii: S0960-9822(25)01000-0. [Epub ahead of print]

Corrections in single-cell migration path in vivo are controlled by pulses in polar Rac1 activation.

Dennis Hoffmann, Tal Agranov, Lucas Kühl, Laura Ermlich, Michal Reichman-Fried, Benjamin D Simons, Nir S Gov, Erez Raz.

  Directed migration of single cells is central to a large number of processes in development and adult life. Corrections to the migration path of cells are often characterized by periodic loss of polarity that is followed by the generation of a new leading edge in response to guidance cues, a behavior termed "run and tumble." While this phenomenon is essential for accurate arrival at migration targets, the precise molecular mechanisms responsible for the periodic changes in cell polarity are unknown. To investigate this issue, we employ germ cells in live zebrafish embryos as an in vivo model and show that a tunable molecular network controls periodic pulsations of Rac1 activity and actin polymerization. This process, which we term "polar pulsations," is responsible for the transitions between the run and tumble phases. In addition, we provide evidence for the role of apolar blebbing activity during tumble phases in erasing the memory of the previous front-back polarity of the migrating cell. To understand how the molecular components give rise to this distinct behavior, we develop a minimal mathematical model of the biochemical network that accounts for the observed cell behavior. Together, our in vivo findings and the mathematical model suggest that a pulsatory signaling network regulates the accuracy of individual cell migration.

Keywords:  PGCs; Rac1; actin; cell migration; cell polarity; cellular memory; mathematical modeling; pulsations; run and tumble; zebrafish

DOI:  https://doi.org/10.1016/j.cub.2025.07.063
Nat Aging. 2025 Aug 27.

Oxidative stress response protein delays ovarian aging by promoting stress granule clearance.

DOI: https://doi.org/10.1038/s43587-025-00960-9
EMBO J. 2025 Aug 26.

Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress.

Irene Salas-Armenteros, Maarten Klunder, Wim Vermeulen, Maria Tresini.

  The DNA Damage Response (DDR) is a highly regulated process that safeguards genomic integrity against DNA lesions. Increasing evidence supports a reciprocal relationship between damaged chromatin architecture and the signalling pathways that coordinate the DDR. However, the mechanisms underlying this interplay in response to transcription-blocking DNA lesions remain largely unexplored. Here, we show that stalling of RNA polymerase II (RNAPII) at such lesions induces local chromatin acetylation, mediated primarily by the histone acetyltransferase p300. The resulting chromatin relaxation stimulates the dissociation of mature co-transcriptional spliceosomes from nascent RNA and promotes RNA:DNA hybrid (R-loop) formation, leading to ATM activation. In turn, activated ATM modulates chromatin conformation by phosphorylating histone H2A.X and triggering p38MAPK/MSK1-dependent histone H3S10 phosphorylation. Our findings highlight the cross-regulation between chromatin state and ATM signalling as a key component of the cellular response to transcription stress.

Keywords:  Chromatin acetylation; DNA Damage Response Signalling; R-loops; Spliceosome; Transcription Stress

DOI:  https://doi.org/10.1038/s44318-025-00537-7
Elife. 2025 Aug 21. pii: e84749. [Epub ahead of print]14

Migrating mesoderm cells self-organize into a dynamic meshwork structure during chick gastrulation.

Yukiko Nakaya, Mitsusuke Tarama, Sohei Tasaki, Ayako Isomura-Matoba, Tatsuo Shibata.

  Migration of cell populations is a fundamental process in morphogenesis and disease. The mechanisms of collective cell migration of epithelial cell populations have been well studied. It remains unclear, however, how the highly motile mesenchymal cells, which migrate extensively throughout the embryo, are connected with each other and coordinated as a collective. During chick gastrulation, cells emerging from the primitive streak and migrating in the 3D space between ectoderm and endoderm (mesoderm region) exhibit a novel form of collective migration. Using live imaging and quantitative analysis, such as topological data analysis (TDA), we found that these cells undergo a novel form of collective migration, in which they form a meshwork structure while moving away from the primitive streak. Overexpressing a mutant form of N-cadherin was associated with reduced speed of tissue progression and directionality of the collective cell movement, whereas the speed of individual cells remains unchanged. To investigate how this meshwork arises, we utilized an agent-based theoretical model, which suggests that cell elongation, cell-cell adhesion, and cell density are the key parameters for the meshwork formation. These data provide novel insights into how a supracellular structure of migrating mesenchymal cells may arise in loosely connected cell populations.

Keywords:  chicken; developmental biology; physics of living systems

DOI:  https://doi.org/10.7554/eLife.84749
Nat Chem Biol. 2025 Aug 26.

Oncometabolite 5-IP7 inhibits inositol 5-phosphatase to license E-cadherin endocytosis.

Hongyun Zhang, Bobo Zhang, Yuebo Zhao, Yang Su, Yifan Peng, Xiaoli Yang, Hongming Zhao, Hongyu Liu, Jie Feng, Hongjing Pei, Wenyong Zhang, Niu Huang, Kai Jiang, Masatoshi Ito, Guizhen Liu, Nicolas Jork, Karen E Anderson, Li Zhao, Eiichiro Nagata, Henning J Jessen, Philip T Hawkins, Changzheng Du, Feng Rao.

E-cadherin downregulation is an epithelial-mesenchymal transition hallmark canonically attributed to transcriptional repression. Here we delineate a metabolite-driven endocytic route of E-cadherin downregulation in inflammation-associated colorectal cancer (CRC). Specifically, IP6 kinase-2 (IP6K2), a 5-diphosphoinositol pentakisphosphate (5-IP7) synthase upregulated in patients with CRC, is activated via a ROS-Src phosphorylation axis elicited by dextran sulfate sodium (DSS), generating 5-IP7 around adherens junction (AJ) to promote E-cadherin endocytosis and the transcriptional activities of β-catenin. Mechanistically, 5-IP7 inhibits inositol 5-phosphatases such as OCRL to promote PI(4,5)P2-mediated endocytic adaptor recruitment. Depleting 5-IP7 or overexpressing a 5-IP7 binding-deficient OCRL mutant confers resistance to DSS-elicited AJ disruption. Intestinal epithelium-specific IP6K2 deletion attenuates DSS-induced colitis/CRC, whereas an IP6K2 isoform-selective inhibitor protects wild-type but not IP6K2-/- mice against DSS insult. Thus, 5-IP7 is an oncometabolite whose stimulus-dependent synthesis relieves a PI(4,5)P2 dephosphorylation-based endocytic checkpoint, leading to AJ disassembly and protumorigenic β-catenin activation. Targeting IP6K2 could strengthen intestinal epithelial barrier against inflammation and cancer.

DOI: https://doi.org/10.1038/s41589-025-02005-z
Mol Cell. 2025 Aug 21. pii: S1097-2765(25)00620-3. [Epub ahead of print]85(16): 3184-3201.e14

Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation.

Mikołaj Słabicki, Jiho Park, Radosław P Nowak, Shourya S Roy Burman, Jesse Pellman, Charles Zou, Hlib Razumkov, Jeannie Carreiro, Simran Rastogi, Anna Goldstein, Marek M Nagiec, Katherine A Donovan, Jianwei Che, Moritz Hunkeler, Qixiang Geng, Chi-Lin Hsu, Megha Lakshminarayan, Chelsea Shu, Rebecca L Zon, Zuzanna Kozicka, Paul M C Park, Jonathan M Tsai, Hojong Yoon, Lyn H Jones, Adam S Sperling, Nathanael S Gray, Eric S Fischer, Benjamin L Ebert.

  Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4CRBN to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has been characterized, it does not fully explain substrate specificity. To explore the role of residues adjacent to this core motif, we constructed a comprehensive ZF reporter library of 9,097 reporters derived from 1,655 human ZF proteins and conducted a library-on-library screen with 29 glutarimide analogs to identify compounds that collectively degrade 38 ZF reporters. Cryo-electron microscopy and crystal structures of ZFs in complex with CRBN revealed the importance of interactions beyond the core ZF degron. We used systematic mutagenesis of ZFs and CRBN to identify modes of neosubstrate recruitment requiring distinct amino acids. Finally, we found subtle chemical variations in glutarimide analogs that alter target scope and selectivity, thus providing a roadmap for their rational design.

Keywords:  CRBN; CRL4(CRBN) E3 ligase; ZF; cereblon; degron specificity; flow-based sorting screens; functional genomics; glutarimide analogs; molecular glue; targeted protein degradation; zinc finger proteins

DOI:  https://doi.org/10.1016/j.molcel.2025.07.019
Nat Commun. 2025 Aug 24. 16(1): 7898

The cAMP-PKA signaling initiates mitosis by phosphorylating Bora.

Min Zhu, Shinan Zhou, Yingqi Zhang, Qinfu Chen, Xueying Yuan, Long Zhang, Haiyan Yan, Fangwei Wang.

Timely entry into mitosis requires activation of Polo-like kinase 1 (Plk1) by Aurora kinase A (Aurora A), but the upstream signaling trigger remains unclear. Here, we show that cyclic AMP (cAMP) signaling serves as a critical initiator of mitosis in mammalian cells. Specifically, the cAMP-dependent protein kinase (PKA) phosphorylates Bora, enabling it to bind Aurora A and recruit it to the Bora-Plk1 complex during G2 phase, thereby facilitating Aurora A-dependent activation of Plk1. Disruption of PKA-mediated Bora phosphorylation or the Bora-Aurora A interaction impairs Plk1 activation and delays the G2-to-mitosis (G2/M) transition. Conversely, a phospho-mimetic Bora mutant bypasses the requirement for PKA in promoting Bora-Aurora A interaction, Plk1 activation, and mitotic entry. Furthermore, PKA-mediated Bora phosphorylation and the resulting Bora-Aurora A interaction are essential for mitotic entry during DNA damage checkpoint recovery. Together, these findings identify the cAMP-PKA-Bora-Aurora A-Plk1 signaling cascade as a previously unrecognized and critical trigger for mitotic commitment.

DOI: https://doi.org/10.1038/s41467-025-63352-y
Sci Adv. 2025 Aug 29. 11(35): eadv9759

Cells prioritize the regulation of cell mass density.

Jinyu Fu, Qin Ni, Yufei Wu, Anoushka Gupta, Zhuoxu Ge, Hongru Yang, Yasin Afrida, Ishan Barman, Sean X Sun.

A cell's global physical state is characterized by its volume and dry mass. The ratio of cell mass to volume defines the cell mass density (CMD), which is also a measure of macromolecular crowding and concentrations of all proteins. Using the fluorescence eXclusion method (FXm) and quantitative phase microscopy (QPM), we investigate CMD dynamics following sudden changes in media osmolarity. We find that while cell volume and mass exhibit complex behavior after osmotic shock, CMD follows a straightforward monotonic recovery over 48 hours. This recovery is cell cycle independent and depends on coordinated adjustment of protein synthesis and volume growth rates. Unexpectedly, the protein synthesis rate decreases when CMD increases. We observe that nucleoplasm-cytoplasm transport is CMD dependent, which contributes to negative regulatory feedback on CMD. The Na+/H+ exchanger helps regulate CMD by affecting both protein synthesis and volume change. Together, we reveal that cells have a robust control system that actively regulates CMD during environmental change.

DOI: https://doi.org/10.1126/sciadv.adv9759
Nat Commun. 2025 Aug 22. 16(1): 7852

Episodic transport of protein aggregates achieves a positive size selectivity in aggresome formation.

Rui Fang, Luolan Bai, Bert M Verheijen, Boyan Li, Kevin Dong, Joao A Paulo, Mengying Zhou, Yi-Chi Chu, Yuyu Song, Michael Y Sherman, Steven Gygi, Christine M Field, Timothy J Mitchison, Ying Lu.

Eukaryotic cells direct toxic misfolded proteins to various quality control pathways based on their chemical properties and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the "aggresome", a perinuclear inclusion at the microtubule-organizing center (MTOC). However, the mechanism for selective aggresome recruitment remains unclear. To investigate this process, here we reconstitute MTOC-directed aggregate transport in Xenopus laevis egg extract using AgDD, a chemically inducible aggregation system. High-resolution single-particle tracking reveals that dynein-mediated aggregate transport is highly episodic, with average velocity positively correlating with aggregate size. Mechanistic modeling suggests that recurrent formation of the dynein transport complex biases larger aggregates towards active transport, compensating for the slowdown due to viscosity. Both episodic transport and positive size selectivity are conferred by aggresome-specific dynein adapters. Coupling an aggresome adapter to polystyrene beads recapitulates positive size selectivity in transport, while recruiting conventional dynein adapters to protein aggregates perturbs aggresome formation and reverses the size selectivity.

DOI: https://doi.org/10.1038/s41467-025-62751-5
Nat Aging. 2025 Aug 20.

Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength.

Peter Vrtačnik, Lara G Merino, Santhilal Subhash, Hafdís T Helgadóttir, Matthieu Bardin, Fabiana Stefani, Depin Wang, Ping Chen, Irene Franco, Gwladys Revêchon, Maria Eriksson.

Aging is associated with a progressive decline in tissue function and regenerative capacity, partly due to genomic instability, one of the hallmarks of aging1,2. Genomic instability encompasses DNA damage and the accumulation of somatic mutations in post-zygotic cells, yet the specific impact of these mutations on age-related tissue dysfunction remains poorly understood. To address this, we developed a mouse model in which genomic instability was induced specifically in muscle progenitor cells3 through targeted deletion of the Msh2 (ref. 4) and Blm5 genes. This allowed us to assess how elevated DNA damage and somatic mutations, from single-nucleotide variants (SNVs) to structural variants, affect muscle regeneration following injury. These mice exhibited impaired muscle regeneration, characterized by smaller muscle fibers, reduced muscle mass gain and decreased grip strength. Importantly, similar muscle deficits were observed in a second mouse model where somatic mutations were elevated with less substantial DNA damage. These findings provide evidence that the accumulation of somatic mutations can potentially compromise the function of somatic cells, contributing to the aging phenotype in skeletal muscle.

DOI: https://doi.org/10.1038/s43587-025-00941-y
Nat Aging. 2025 Aug 26.

Mevalonate metabolites boost aged oocyte quality through prenylation of small GTPases.

Chuanming Liu, Huidan Zhang, Jialian Mao, Sainan Zhang, Xiao Tian, Yibing Zhu, Changjiang Wang, Junshun Fang, Huijie Pan, Nannan Kang, Yang Zhang, Jidong Zhou, Xin Zhen, Guijun Yan, Chaojun Li, Yali Hu, Cunqi Ye, Ran Xie, Chun So, Haixiang Sun, Lijun Ding.

Declining oocyte quality is the major contributor to female subfertility in aged mammals. Currently, there are no effective interventions to ameliorate aged oocyte quality. Here we found that oocytes at metaphase I from the cumulus-oocyte complexes of aged mice showed reduced cortical F-actin and lower levels of mevalonate (MVA) pathway metabolites, including MVA, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate. We further showed that MVA supplementation improved FPP levels, cortical F-actin and the quality of aged oocytes. Mechanistically, we found that MVA supplementation induced granulosa cells to synthesize FPP, which was subsequently transferred to aged oocytes. Transported FPP increased the prenylation of small GTPases, including CDC42 and RAC1, and promoted membrane localization of CDC42-N-WASP-Arp2/3 and RAC1-WAVE2-Arp2/3 complexes, promoting cortical F-actin reassembly and reducing aneuploidy of aged oocytes. We also identified a natural chemical compound, 8-isopentenyl flavone, with an isopentenyl side chain from Epimedium brevicornu Maxim, which could increase CDC42 and RAC1 prenylation, improving the cortical F-actin and the competence of aged oocytes, and ameliorating reproductive outcomes in aged female mice. Collectively, increasing the prenylation of small GTPases via MVA metabolites or 8-isopentenyl flavone provides a therapeutic approach for boosting female fertility during reproductive aging.

DOI: https://doi.org/10.1038/s43587-025-00946-7
Mol Cell. 2025 Aug 19. pii: S1097-2765(25)00659-8. [Epub ahead of print]

A regulator of amino acid sensing links lipid peroxidation and lipid droplet-dependent antioxidant response.

Jinhua Li, Yansong Zhang, Jingyu Peng, Wei Yang, Yanzhe Pan, Ying Xu, Jiayi Yao, Siyuan Lin, Yizhi Li, Xinran Gu, Wei Dong, Xiang Yu, Ming Ge, Min Liu, Alan Jian Zhu.

  Recent studies highlight the antioxidant role of lipid droplets (LDs) in shielding unsaturated lipids from peroxidation. While LDs accumulate during oxidative stress, the underlying mechanism remains unclear. Our previous research revealed that intracellular amino acids directly bind to and activate the E3 ubiquitin ligase Ubr1 to degrade Plin2, an LD protein inhibiting lipolysis. Here, we unexpectedly find that Ubr1's ability to bind to amino acids is inhibited during oxidative stress. Mechanistically, oxidative stress-induced lipid peroxidation blocks the activity of Hsc70-4, an ATPase that maintains the amino-acid-binding ability of Ubr1. 4-hydroxynonenal, a reactive product of lipid peroxidation, covalently modifies and inactivates Hsc70-4, leading to Ubr1 inactivation, Plin2 stabilization, and LD accumulation. Increased LDs minimize lipid peroxidation, thus protecting cells from oxidative damage and cell death. Together, we identify a regulator of amino acid sensing with redox-dependent activity, bridging the gap in understanding how lipid peroxidation stimulates LD-dependent antioxidant responses.

Keywords:  4-hydroxynonenal; HSPA8; Hsc70-4; Plin2; Ubr1; amino acid sensing; antioxidant response; lipid droplet; lipid peroxidation

DOI:  https://doi.org/10.1016/j.molcel.2025.08.009
Sci Adv. 2025 Aug 22. 11(34): eadw2470

Efficient termination of transcription by RNA polymerase I requires a conserved hairpin of the ribosomal RNA precursor.

Soren Nielsen, Nikolay Zenkin.

RNA polymerase I (Pol I) synthesizes ribosomal RNA precursor (pre-rRNA), which comprises most of RNA in eukaryotic cells. Despite decades of investigation, there is still no consensus on what causes Pol I transcription termination. Here, we show that efficient termination by Pol I, paused by termination roadblock protein, is caused by RNA hairpin of the nascent pre-rRNA. Hairpin-dependent termination takes place at a physiological rate and does not require trans-acting factors. The function of the roadblock protein and the T-rich sequence is to synergistically cause deep backtracking of Pol I toward the termination RNA hairpin. Simultaneously, Pol I is catalytically inactivated, preventing rescue from backtracking through RNA cleavage and thus committing Pol I to termination. Termination RNA hairpins are present in most of Pol I terminators of eukaryotes, suggesting conservation of the RNA hairpin-dependent mechanism of Pol I transcription termination. We propose a simple model that unifies previous findings.

DOI: https://doi.org/10.1126/sciadv.adw2470
Nat Commun. 2025 Aug 22. 16(1): 7858

Early lineage segregation of primary myotubes from secondary myotubes and adult muscle stem cells.

Gauthier Toulouse, William Jarassier, Sabrina Jagot, Valérie Morin, Fabien Le Grand, Christophe Marcelle.

Myogenesis in amniotes occurs in two waves. Primary myotubes express slow myosin (often with fast myosin) and likely act as scaffolds for secondary myotubes, which express only fast myosin. The embryonic origins and relationships of these lineages, and their connection to satellite cells, remain unknown. Here, we combine a TCF-LEF/β-catenin signaling reporter with precise in vivo electroporation in avian embryos to trace limb muscle progenitors from early migration to fetal stages. We identify two distinct progenitor populations that coexist from the onset: reporter-positive cells give rise exclusively to primary myotubes, while reporter-negative cells generate secondary myotubes and satellite cells. We also reveal a previously unrecognized role for TCF-LEF/β-catenin signaling in spatially organizing the primary lineage via Cxcr4-mediated control of myoblast migration. These findings redefine the developmental origin of myogenic lineages, resolve a longstanding question in muscle biology, and provide a molecular framework for investigating how muscle fiber diversity emerges and how distinct lineages contribute to the functional specialization of skeletal muscle.

DOI: https://doi.org/10.1038/s41467-025-61767-1
Cell. 2025 Aug 13. pii: S0092-8674(25)00863-3. [Epub ahead of print]

Adenosine kinase and ADAL coordinate detoxification of modified adenosines to safeguard metabolism.

Akiko Ogawa, Satoshi Watanabe, Iuliia Ozerova, Allen Yi-Lun Tsai, Yoshihiko Kuchitsu, Harrison Byron Chong, Tomoyoshi Kawakami, Jirio Fuse, Wei Han, Ryuhei Kudo, Tomoki Naito, Kota Sato, Toru Nakazawa, Yasunori Saheki, Akiyoshi Hirayama, Peter F Stadler, Mieko Arisawa, Kimi Araki, Liron Bar-Peled, Tomohiko Taguchi, Shinichiro Sawa, Kenji Inaba, Fan-Yan Wei.

  RNA contains diverse post-transcriptional modifications, and its catabolic breakdown yields numerous modified nucleosides requiring correct processing, but the mechanisms remain unknown. Here, we demonstrate that three RNA-derived modified adenosines, N6-methyladenosine (m6A), N6,N6-dimethyladenosine (m6,6A), and N6-isopentenyladenosine (i6A), are sequentially metabolized into inosine monophosphate (IMP) to mitigate their intrinsic cytotoxicity. After phosphorylation by adenosine kinase (ADK), they undergo deamination by adenosine deaminase-like (ADAL). In Adal knockout mice, N6-modified adenosine monophosphates (AMPs) accumulate and allosterically inhibit AMP-activated protein kinase (AMPK), dysregulating glucose metabolism. Furthermore, ADK deficiency, linked to human inherited disorders of purine metabolism, elevates levels of the three modified adenosines, resulting in early lethality in mice. Mechanistically, excessive m6A, m6,6A, and i6A impair lysosomal function by interfering with lysosomal membrane proteins, thereby disrupting lipid metabolism and causing cellular toxicity. Through this nucleotide metabolism pathway and mechanism, cells detoxify modified adenosines, linking modified RNA metabolism to human disease.

Keywords:  ADAL; ADK; AMP-activated protein kinase; AMPK; Adenosine deaminase-like; Adenosine kinase; Lipid metabolism; Lysosome; Modified RNA metabolism; Purine metabolism; RNA modification; m(6)A

DOI:  https://doi.org/10.1016/j.cell.2025.07.041
Nat Cell Biol. 2025 Aug 25.

CHIP protects lysosomes from CLN4 mutant-induced membrane damage.

Juhyung Lee, Natalie Chin, Jizhong Zou, Wan Nur Atiqah Binti Mazli, Michal Jarnik, Layla Saidi, Yue Xu, Eutteum Jeong, Jessica Suh, John Replogle, Michael E Ward, Juan S Bonifacino, Wei Zheng, Ling Hao, Yihong Ye.

Understanding how cells mitigate lysosomal damage is critical for unravelling pathogenic mechanisms of lysosome-related diseases. Here we generate and characterize induced pluripotent stem cell (iPSC)-derived neurons (i3Neuron) bearing ceroid lipofuscinosis neuronal 4 (CLN4)-linked DNAJC5 mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosomal damages caused by lysosome-associated CLN4 mutant aggregates, as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP's lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i3Neurons and effectively alleviates lipofuscin accumulation and cell death in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, offering new insights into therapeutic development for lysosome-related neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41556-025-01738-2
Nat Commun. 2025 Aug 20. 16(1): 7438

Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis.

Jeremy Williams, Roman Camarda, Serghei Malkov, Lisa J Zimmerman, Suzanne Manning, Dvir Aran, Andrew Beardsley, Daniel Van de Mark, Rachel Nakagawa, Yong Chen, Charles Berdan, Sharon M Louie, Celine Mahieu, Daphne Superville, Juliane Winkler, Elizabeth Willey, Erica J Hutchins, John D Gagnon, Seda Kilinc Avsaroglu, Kosaku Shinoda, Matthew Gruner, Hiroshi Nishida, K Mark Ansel, Zena Werb, Daniel K Nomura, Shingo Kajimura, Atul J Butte, Melinda E Sanders, Daniel C Liebler, Hope S Rugo, Gregor Krings, John A Shepherd, Andrei Goga.

A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 (GJB3) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer.

DOI: https://doi.org/10.1038/s41467-025-62486-3
Nat Commun. 2025 Aug 25. 16(1): 7929

Epsin1 enforces a condensation-dependent checkpoint for ubiquitylated cargo during clathrin-mediated endocytosis.

Susovan Sarkar, Hao-Yang Liu, Feng Yuan, Brandon T Malady, Liping Wang, Eileen M Lafer, Jessica Perez, Jon M Huibregtse, Jeanne C Stachowiak.

Clathrin-mediated endocytosis internalizes proteins and lipids from the cell surface. A flexible condensate of initiator proteins catalyzes assembly of clathrin-coated vesicles in diverse organisms. Here we reveal that an endocytic adaptor protein, Epsin1, conditionally stabilizes this network, creating a cargo-dependent endocytic checkpoint. Epsin1 recruits ubiquitylated cargo to endocytic sites. Using in vitro assays, we demonstrate that Epsin1 destabilizes condensation of initiator proteins in the absence of ubiquitin. However, when polyubiquitin is present, Epsin1 binds to both ubiquitin and initiator proteins, stabilizing condensation. Similarly, in mammalian cells, endocytosis is disrupted by removal of either ubiquitin or Epsin1. When both components are removed simultaneously, endocytic defects are largely rescued, although the ability to preferentially internalize ubiquitylated cargo is lost. These results suggest that Epsin1 tunes protein condensation to internalize ubiquitylated cargo. More broadly, these findings illustrate how a balance of attractive and repulsive molecular interactions can exert dynamic control over cellular events.

DOI: https://doi.org/10.1038/s41467-025-63238-z
Nat Commun. 2025 Aug 25. 16(1): 7901

DNA double-strand break end resection factors and WRN facilitate mitotic DNA synthesis in human cells.

Szymon A Barwacz, Katrine Lundgaard, Wei Wu, Philipp H Richter, Liqun Ren, Rahul Bhowmick, Marisa M Gonçalves Dinis, Masato T Kanemaki, Ying Liu.

Mitotic DNA synthesis (MiDAS) serves to complete the replication of genomic loci that are not fully replicated in S phase in response to replication stress. Previous studies suggest that MiDAS might proceed via break-induced DNA replication, a sub-pathway of homologous recombination repair activated at broken or collapsed replication forks. We set out to define whether DNA double strand break end-resection factors play a role in MiDAS. Here, we show that several core end-resection factors, including MRE11, CtIP and BRCA1 are essential for MiDAS. In addition, while loss of WRN or DNA2 impairs MiDAS, there is no requirement for other known end-resection factors such as EXO1 and BLM. Moreover, both the exonuclease and the helicase activities of WRN contribute to MiDAS. Because oncogene-induced replication stress is common in cancers, targeting of WRN or other factors required for MiDAS could facilitate the development of targeted cancer therapies.

DOI: https://doi.org/10.1038/s41467-025-63292-7
Nat Cell Biol. 2025 Aug 27.

A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy.

Mario Mauthe, Nicole van de Beek, Muriel Mari, Giel Korsten, Parisa Nobari, Kennith B Castelino, Eduardo P de Mattos, Ibtisam Ouhida, Jesse L Dijkstra, Sabine Schipper-Krom, Laura R de la Ballina, Monja R Mueller, Anne Simonsen, Mark S Hipp, Lukas C Kapitein, Harm H Kampinga, Fulvio Reggiori.

Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.

DOI: https://doi.org/10.1038/s41556-025-01747-1
J Invest Dermatol. 2025 Aug 22. pii: S0022-202X(25)02352-8. [Epub ahead of print]

High-Resolution Spatial Transcriptomics Unveils Spatially Resolved Gene Modules and Fatty Acid Metabolism Dysregulation in Human Skin Aging.

Yin Li, Wenwan Zhang, Yao Teng, Xia Zhang, Sweelin Chew, Yang Liu, Peng Hua, Tingting Yu, Yuao Yan, Yu Bu, Yidan Sun, Luwen Xu, Qiaoyu Fu, Lifang Lei, Yining Chen, Zhengcheng Liu, Caibing Wang, Peiying Zhu, Yao Yu, Nan Huang, Qingfeng Li, Caiyue Liu, Liang Zhang.

  Human skin aging involves intricate micrometer-scale changes in cellular organization. High-resolution spatial transcriptomic analysis is crucial for deciphering the complex interplay of cell types and molecular processes underlying skin aging. Here, the Stereo-seq technique was employed to generate a high-resolution spatial transcriptomic atlas of human eyelid skin, capturing age-related alterations in gene expression. Integrating this atlas with multiplexed fluorescent in situ hybridization (FISH), we spatially mapped known cells population, identified 8 spatial tissue clusters, and uncovered 18 spatially correlated gene modules in human skin. Our analysis revealed that human eyelid skin aging is characterized not only by dermal atrophy and chronic inflammation, but also by reduced dermal-epidermal communication, decreased epidermal fatty acid (FA) synthesis, potential loss of epidermal cell identity, and diminished c-FOS expression in epidermis. Functional studies using primary human keratinocytes and a reconstructed full-thickness skin model (T-SkinTM) demonstrated that reduced activity of FA synthesis enzymes FDPS and FASN promoted epidermal senescence and barrier dysfunction. This spatially resolved transcriptomic analysis provides, to our knowledge, previously unreported insights into the molecular mechanism driving skin aging, offering potential target for aging intervention strategies.

Keywords:  Human skin; Skin aging; Spatial transcriptomics; Stereo-seq

DOI:  https://doi.org/10.1016/j.jid.2025.08.011