bims-ginsta Biomed News
on Genome instability
Issue of 2026–01–11
forty-one papers selected by
Jinrong Hu, National University of Singapore
  1. Genetically engineered ESC-derived embryos reveal Vinculin-dependent force responses required for mammalian neural tube closure.
  2. A mechanical ratchet drives unilateral cytokinesis.
  3. Lamin A/C directs nucleosome-scale chromatin remodeling to define early lineage segregation in mammals.
  4. Developmental regulation of Erk signaling by mitotic kinases.
  5. p53 increases phospholipid headgroup scavenging in senescence.
  6. Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
  7. Cell-cycle-dependent repression of histone gene transcription by histone H4.
  8. Membrane curvature initiates Cdc42-FBP17-N-WASP clustering and actin nucleation.
  9. Plasma membrane-to-lysosome FGR signaling regulates endocytosis-associated lysosome homeostasis.
  10. R-loops orchestrate RNAPII transcriptional reprogramming for the maternal-to-zygotic transition.
  11. TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis.
  12. Optogenetic Proximity Labeling Maps Spatially Resolved Mitochondrial Surface Proteomes and a Locally Regulated Ribosome Pool.
  13. Extracellular matrix restrains cell-cycle progression by nuclear exclusion of Yorkie in Drosophila.
  14. EcDNA-borne structural variants drive oncogenic fusion transcript amplification.
  15. NIPBL-mediated 3D genome folding translates enhancer priming into gene activation and safeguards lineage fidelity during embryonic transitions.
  16. PARG regulates the proteasomal degradation of TARG1.
  17. Nutrient requirements of organ-specific metastasis in breast cancer.
  18. ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis.
  19. IFI16 senses and protects stalled replication forks.
  20. RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress.
  21. Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.
  22. Redox-driven ADAR1 activation promotes Okazaki fragment maturation and DNA replication integrity.
  23. A peripheral glial niche orchestrates the early stages of skin wound healing.
  24. Stress-induced loss of CTCF reveals an alternative, promoter-based mode of cohesin looping.
  25. Mammalian metaphase kinetochores are elastic and require condensin for robust structure and function.
  26. Mitochondrial control of fuel switching via carnitine biosynthesis.
  27. Membrane-protein-mediated phase separation orchestrates organelle contact sites.
  28. Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry.
  29. Dual pathways via CENP-C and Mis18C recruit HJURP for CENP-A deposition into vertebrate centromeres.
  30. Inhibition of Annexin A2 Facilitates PHB2-Mediated Mitophagy in Cardiomyocytes to Alleviate Cardiac Injury and Remodeling After Infarction.
  31. Oxidative stress and GPX2 control pancreatic vs. non-pancreatic cell fate in human endoderm.
  32. CUL4A-DDB1-DCAF10 is an N-recognin for N-terminally acetylated Src kinases.
  33. Extracellular BRICK1 drives heart repair after myocardial infarction in mice.
  34. HP1 isoforms direct repair pathway choice in response to heterochromatin double-strand breaks.
  35. The adipose tissue has an apical-basal polarity required for Col IV-dependent cell-cell adhesion.
  36. Condensin II collaborates with cohesin to establish and maintain interphase chromosome territories.
  37. Keratin 15 promotes a progenitor cell state in basal keratinocytes of skin epidermis.
  38. Friction-driven scission: How nonlocal mechanisms contribute to membrane fission across domains of life.
  39. Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors.
  40. Biological clocks keep a watch on mitosis.
  41. Dynamins maintain nuclear envelope homeostasis and genome stability.
  1. bioRxiv. 2025 Dec 25. pii: 2025.12.22.696028. [Epub ahead of print]
    Genetically engineered ESC-derived embryos reveal Vinculin-dependent force responses required for mammalian neural tube closure.
    Ian S Prudhomme, Eric R Brooks, Nilay Taneja, Bhaswati Bhattacharya, Brian J LaFleche, Yasuhide Furuta, Jennifer A Zallen.
      Epithelial sheets build complex structures by converting mechanical forces into changes in cell and tissue organization. During neural tube closure, the neural plate dynamically remodels to produce a closed tube that provides the structural foundation for the developing brain and spinal cord. How cells maintain epithelial integrity despite the forces required for tissue morphogenesis during neural tube closure is not understood. We show that mechanical forces are upregulated during cranial neural tube closure in the mouse embryo and recruit the force-sensitive protein Vinculin to adherens junctions. Leveraging a genetically engineered embryonic stem cell-based pipeline to efficiently generate mutant embryos, we show that Vinculin mutants produce mechanical forces correctly but fail to maintain cell adhesion under tension, resulting in a failure of cranial neural fold elevation. Live imaging of cell behavior in the developing midbrain reveals that apical constriction, cell rearrangement, and cell division initiate correctly in Vinculin mutants, but their progression is impeded by disruption of adherens junctions at sites of increased tension. These results demonstrate that Vinculin is required to reinforce cell adhesion in response to increasing physiological forces during cranial neural tube closure, and that this activity is necessary to translate these forces into changes in tissue structure.
    DOI:  https://doi.org/10.64898/2025.12.22.696028
  2. Nature. 2026 Jan 07.
    A mechanical ratchet drives unilateral cytokinesis.
    Alison Kickuth, Urša Uršič, Michael F Staddon, Jan Brugués.
      The canonical mechanism that drives cell division comprises the formation and constriction of a contractile actin ring1-3. However, this mechanism is not compatible with the early development of many vertebrates4-9. Yolk-anchored embryos typically cannot form a complete ring during early cleavage divisions, but it remains unclear how a partial circular arc with loose ends can divide the cell. Here, by combining laser ablation of the cytokinetic band with rheological measurements in vivo, we show that stiffening of the bulk cytoplasm, mediated by the interphase microtubule network, stabilizes the contractile band by anchoring it along its length during growth. Conversely, as the cell cycle progresses, the cytoplasm fluidizes, diminishing band-cytoplasmic anchoring and facilitating band ingression. This dynamic interplay between stability and growth versus instability and ingression repeats for several cell cycles until division is complete, resulting in a mechanical ratchet that drives cell division. Our study underscores the role of temporal control over cytoplasmic rheology as a key feature that drives unilateral cytokinesis in the absence of a closed actin ring.
    DOI:  https://doi.org/10.1038/s41586-025-09915-x
  3. bioRxiv. 2026 Jan 02. pii: 2026.01.01.696913. [Epub ahead of print]
    Lamin A/C directs nucleosome-scale chromatin remodeling to define early lineage segregation in mammals.
    Alice Sherrard, Liangwen Zhong, Caroline Hoppe, Srikar Krishna, Scott Youlten, Curtis W Boswell, Stephen Cross, Fiona E Sievers, Goli Ardestani, Denny Sakkas, Liyun Miao, Zachary D Smith, Berna Sozen, Antonio J Giraldez.
      Chromatin organization underlies gene regulation and cell fate specification, yet how nucleosome-scale chromatin structure contributes to lineage segregation during early development remains unknown. Here, we resolved chromatin ultrastructure during the first lineage decision in mouse and human, which forms the pluripotent inner cell mass (ICM) and trophectoderm (TE). To achieve this, we developed dual-tilt chromatin electron tomography (2T-ChromEMT) that allows multiscale visualization of chromatin architecture. Our analysis reveals that TE cells of both species display denser chromatin with nucleosome aggregation at the nuclear periphery. We show upregulation of the nuclear matrix protein Lamin A/C within the TE lineage across mouse, human, and opossum embryos, indicating that its regulatory role is conserved across eutherian and marsupial species. Loss of Lamin A/C reduces heterochromatin at the nuclear lamina in TE cells, reactivates pluripotency genes, and impairs mouse blastocyst expansion and human blastoid formation. These findings define the nucleosome-resolution chromatin signatures of early mammalian lineages and establish Lamin A/C-mediated chromatin organization as a conserved mechanism in the exit from pluripotency and maintenance of trophectoderm identity.
    DOI:  https://doi.org/10.64898/2026.01.01.696913
  4. Sci Adv. 2026 Jan 09. 12(2): eadq7469
    Developmental regulation of Erk signaling by mitotic kinases.
    Fei Chen, Jan M Bruder, Niraimathi Govindasamy, Jie Wu, Rui Chen, Devila Prit, Hannes C A Drexler, Sebastian A Leidel, Hans R Schöler, Ivan Bedzhov.
      During the peri-implantation phase of murine embryogenesis, the epiblast proliferates rapidly and undergoes epithelialization. At the same time, the preimplantation pluripotent state transforms into a more developmentally advanced, pregastrulation state. While extensive research has elucidated cell-extrinsic signals that direct the developmental progression, such as the Fgf/Mek/Erk pathway, the potential interplay of intrinsic cellular cues remains largely unexplored. To address this, we conducted a comprehensive phenotypic screen using an in vitro model of epiblast development. We identified aurora kinase A as a cell-intrinsic factor contributing to Erk activation and transcriptional response. Consequently, suppressing aurora kinase A activity delayed exit from naïve pluripotency. Moreover, our results show that upon entry into mitosis, Erk relocates to the cell division machinery. We found that in dividing cells, a fraction of Erk, with yet elusive functions, localizes on the centrosomes, where its phosphorylation depends on polo-like kinase 1.
    DOI:  https://doi.org/10.1126/sciadv.adq7469
  5. Nat Cell Biol. 2026 Jan 07.
    p53 increases phospholipid headgroup scavenging in senescence.
    Jossie J Yashinskie, Xianbing Zhu, Grace H McGregor, Karl A Wessendorf-Rodriguez, Katrina Paras, Julia S Brunner, Benjamin T Jackson, Abigail Xie, Richard Koche, Christian M Metallo, Lydia W S Finley.
      Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR-Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability.
    DOI:  https://doi.org/10.1038/s41556-025-01853-0
  6. Nat Cardiovasc Res. 2026 Jan 06.
    Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.
    Michael R Murphy, Mythily Ganapathi, Esther R Rotlevi, Teresa M Lee, Joshua M Fisher, Megha V Patel, Parul Jayakar, Amanda Buchanan, Alyssa L Rippert, Rebecca C Ahrens-Nicklas, Divya Nair, Shalini S Nayak, Aakanksha Anand, Anju Shukla, Rajesh K Soni, Yue Yin, Feiyue Yang, Enrique J Garcia, Muredach P Reilly, Wendy K Chung, Xuebing Wu.
      The heart uses a muscle-specific ribosome in cardiomyocytes, where the ribosomal protein RPL3 is replaced by its paralog RPL3L. Rare biallelic RPL3L mutations cause fatal neonatal dilated cardiomyopathy, yet the mechanisms that link genotype to heart failure are unclear. Despite the recessive inheritance pattern in humans, Rpl3l knockout mice show no overt cardiac phenotype, probably because of compensatory RPL3 upregulation through unknown mechanisms. Here we report four additional cases and propose a unifying pathogenetic model by integrating human genetics, patient tissues and isogenic cell models. Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele. Whereas non-hotspot variants phenocopy knockout and allow RPL3 compensation, hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation by preserving the role of RPL3L in repressing RPL3 via unproductive splicing. These findings establish combined loss-of-function and gain-of-function mechanisms for RPL3L-associated cardiomyopathy and inform genetic screening, diagnosis and therapeutic development.
    DOI:  https://doi.org/10.1038/s44161-025-00761-8
  7. Nat Struct Mol Biol. 2026 Jan 05.
    Cell-cycle-dependent repression of histone gene transcription by histone H4.
    Kami Ahmad, Matt Wooten, Brittany N Takushi, Velinda Vidaurre, Xin Chen, Steven Henikoff.
      In all eukaryotes, DNA replication is coupled to histone synthesis to coordinate chromatin packaging of the genome. Canonical histone genes coalesce in the nucleus into the histone locus body (HLB), where gene transcription and 3' mRNA processing occurs. Both histone gene transcription and mRNA stability are reduced when DNA replication is inhibited, implying that the HLB senses the rate of DNA synthesis. In Drosophila melanogaster, the S-phase-induced histone genes are tandemly repeated in an ~100 copy array, whereas, in humans, these histone genes are scattered. In both organisms, these genes coalesce into HLBs. Here, we use a transgenic histone gene reporter and RNA interference in Drosophila to identify canonical H4 histone as a unique repressor of histone synthesis during the G2 phase in germline cells. Using cytology and CUT&Tag chromatin profiling, we find that histone H4 uniquely occupies histone gene promoters in both Drosophila and human cells. Our results suggest that repression of histone genes by soluble histone H4 is a conserved mechanism that coordinates DNA replication with histone synthesis in proliferating cells.
    DOI:  https://doi.org/10.1038/s41594-025-01731-1
  8. EMBO J. 2026 Jan 03.
    Membrane curvature initiates Cdc42-FBP17-N-WASP clustering and actin nucleation.
    Kexin Zhu, Xiangfu Guo, Aravind Chandrasekaran, Xinwen Miao, Padmini Rangamani, Wenting Zhao, Yansong Miao.
      The architecture of actin networks at the cell surface is regulated by local membrane topology. However, how actin nucleation can respond sensitively to the degree of membrane curvature remains incompletely understood. Using nanolithography to precisely control local membrane curvature, we reconstituted the dynamic interplay of the tri-component Cdc42/FBP17/N-WASP system on a series of deformed membrane sites, resulting in differential actin nucleation. We found that high-curvature sensing is primarily mediated by FBP17 through its intrinsic BAR-domain activity, which then induces the hierarchical assembly of FBP17/N-WASP clusters to activate N-WASP in synergy with Cdc42. This nucleation boost is fine-tuned by modulating the FBP17-to-N-WASP stoichiometry within multivalent macromolecular assemblies according to local curvature radii. At lower-curvature regions, Cdc42 enhances basal FBP17 recruitment to the membrane, enabling detection of shallow curvatures and initiating actin polymerization before high-curvature effects dominate. This establishes a dynamic, curvature radius-dependent cooperativity that links geometric cues to the regulation of actin polymerization, highlighting their interplay in coordinating membrane and actin morphodynamics during complex cellular processes.
    Keywords:  Actin Polymerization; Membrane Curvature; Multivalent Interaction
    DOI:  https://doi.org/10.1038/s44318-025-00677-w
  9. J Cell Biol. 2026 Mar 02. pii: e202506139. [Epub ahead of print]225(3):
    Plasma membrane-to-lysosome FGR signaling regulates endocytosis-associated lysosome homeostasis.
    Qiuyuan Yin, Jifan Qian, Xiao Ding, Xiaoxia Ren, Shalan Li, Zonghao Zhang, Meijiao Li, Long Xiao, Zhiguo Zhang, Fan Lai, Xuna Wu, Xiaojiang Hao, Chonglin Yang.
      Transcriptional control of lysosome biogenesis is an important mechanism underlying cellular adaptation to stress. It is largely unclear how cell surface changes or signals induce alteration in lysosome numbers. By developing a Caenorhabditis elegans-based heterologous TFE3 activation system, we here identify the non-receptor tyrosine kinases SRC-1/-2 (C. elegans) and FGR (mammals) as critical regulators of lysosome biogenesis. In C. elegans, inactivation of src-1/-2 leads to nuclear enrichment of ectopically expressed TFE3 and increased intensity of lysosomal markers. In mammalian cells, FGR inhibition or deficiency similarly results in TFEB/TFE3-dependent lysosomal increase. FGR acts through AKT2 by promoting the activation of the latter. FGR associates with the plasma membrane but is internalized onto endosomes and reaches lysosomes along the endosome-lysosome pathway following endocytosis. Lysosomal FGR promotes AKT2 recruitment to lysosomes, where it phosphorylates TFEB/TFE3 to prevent their activation. Together, these findings reveal a plasma membrane-to-lysosome signaling axis that is required for endocytosis-associated lysosome homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202506139
  10. Cell Res. 2026 Jan 09.
    R-loops orchestrate RNAPII transcriptional reprogramming for the maternal-to-zygotic transition.
    Yaoyi Li, Qing Li, Xinxiu Wang, Chao Di, Yingliang Sheng, Ying Ma, Junzhi Liao, Qingqing Cai, Sainan Huang, Jiayu Chen, Guangming Wu, Lingling Zhang, Guangjin Pan, Shaorong Gao, Hongjie Yao.
      R-loops are pervasive genomic structures that link epigenetic modification and transcriptional regulation. However, the functional roles and regulatory mechanisms of R-loops during preimplantation development in mammals remain unexplored. Here, we reveal that the reprogramming of R-loops across developmental stages depends on CG density, with CG-poor R-loops more stage specific and strongly associated with early embryonic development. Loss of CG-poor R-loops causes severe defects in the maternal-to-zygotic transition (MZT) and preimplantation embryo development. This abnormal maintenance of CG-poor R-loops promotes premature activation of major zygotic genome activation (ZGA) genes. CG-poor R-loops inhibit DDX21 helicase activity on the 7SK/HEXIM1 snRNP complex, restricting CDK9 release and subsequent phosphorylation of Ser2 at the C-terminal domain of RNA polymerase II (RNAPII S2p) - the biochemical hallmark of pause release - thus enforcing RNAPII accumulation at major ZGA gene promoters to ensure productive transcription. These findings establish R-loops as direct modulators of RNAPII pause release, promoting the temporal fidelity of gene expression during the MZT.
    DOI:  https://doi.org/10.1038/s41422-025-01208-2
  11. Nat Cancer. 2026 Jan 05.
    TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis.
    Zhenghan Wang, Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué.
      Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy.
    DOI:  https://doi.org/10.1038/s43018-025-01094-y
  12. bioRxiv. 2025 Dec 23. pii: 2025.12.21.693523. [Epub ahead of print]
    Optogenetic Proximity Labeling Maps Spatially Resolved Mitochondrial Surface Proteomes and a Locally Regulated Ribosome Pool.
    Chulhwan S Kwak, Zehui Du, Joseph S Creery, Emily M Wilkerson, Michael B Major, Joshua E Elias, Xinnan Wang.
      Outer mitochondrial membranes (OMM) function as dynamic hubs for inter-organelle communication, integrating bidirectional signals, and coordinating organelle behavior in a context-dependent manner. However, tools for mapping mitochondrial surface proteomes with high spatial and temporal resolution remain limited. Here, we introduce an optogenetic proximity labeling strategy using LOV-Turbo, a light-activated biotin ligase, to profile mitochondrial surface proteomes with improved precision, temporal control, and reduced background. By fusing LOV-Turbo to a panel of variants of an OMM-anchored protein, Miro1, we generate spatially distinct baits that resolve modular architectures and regulatory states of the OMM proteomes across diverse conditions, a database we name MitoSurf. Building on this proteomic map, we present RiboLOOM, a platform that defines LOV-Turbo labeled ribosomes and their bound mRNAs at the mitochondrial surface. MitoSurf and RiboLOOM uncover a spatially distinct ribosome pool at the OMM that is maintained by Miro1, enabling local mRNA engagement and translation of mitochondria-related proteins. These findings establish Miro1 as a key organizer of mitochondrial protein biogenesis through spatial confinement of surface-associated ribosomes. Our platform reveals an uncharted layer of mitochondrial surface biology and provides a generalizable strategy to dissect dynamic RNA-protein-organelle interfaces in living cells.
    DOI:  https://doi.org/10.64898/2025.12.21.693523
  13. Curr Biol. 2026 Jan 08. pii: S0960-9822(25)01620-3. [Epub ahead of print]
    Extracellular matrix restrains cell-cycle progression by nuclear exclusion of Yorkie in Drosophila.
    Liyuan Sui, Elisabeth Fischer-Friedrich, Christian Dahmann.
      Tissues and organs grow to a characteristic final size during animal development. A hallmark of tissues reaching their final size is the cessation of cell-cycle progression. However, the mechanisms by which cell-cycle progression is halted in tissues reaching their final size remain largely unknown. Here, we show that the extracellular matrix (ECM) is necessary and sufficient to halt cell-cycle progression at G2 phase in Drosophila late-larval-stage wing discs reaching their final size. Depleting ECM in late-larval-stage wing discs leads to nuclear accumulation of the co-transcriptional activator Yorkie (YAP and TAZ in mammals) and to a Yorkie-dependent release of cells from G2-phase arrest. Conversely, increasing ECM thickness induces precocious G2-phase accumulation, which is overcome by expression of an activated form of Yorkie. Furthermore, we show that programmed ECM degradation is necessary for the normal resumption of cell-cycle progression during later pupal stages and for proper adult wing size. Our work identifies a critical role for ECM in restraining cell-cycle progression in tissues reaching their final size and reveals ECM-mediated nuclear exclusion of Yorkie as a key mechanism.
    Keywords:  Drosophila; FUCCI; Yorkie; basement membrane; cell-cycle progression; extracellular matrix; tissue size; wing disc
    DOI:  https://doi.org/10.1016/j.cub.2025.11.079
  14. Cell. 2026 Jan 07. pii: S0092-8674(25)01422-9. [Epub ahead of print]
    EcDNA-borne structural variants drive oncogenic fusion transcript amplification.
    Hyerim Yi, Shu Zhang, Jason Swinderman, Yanbo Wang, Vishnupriya Kanakaveti, King L Hung, Ivy Tsz-Lo Wong, Suhas Srinivasan, Ellis J Curtis, Aarohi Bhargava-Shah, Rui Li, Matthew G Jones, Jens Luebeck, Chris Bailey, Yanding Zhao, Julia A Belk, Katerina Kraft, Quanming Shi, Xiaowei Yan, Simon K Pritchard, Kabir S Mahajan, Frances Liang, Mariam Jamal-Hanjani, Dean W Felsher, Luke A Gilbert, Vineet Bafna, Paul S Mischel, Howard Y Chang.
      Extrachromosomal DNA (ecDNA) amplifications are key drivers of human cancers. Here, we show that ecDNAs are major platforms for generating and amplifying oncogene fusion transcripts across diverse cancer types. By integrating analysis of whole-genome and transcriptome sequences from tumor samples and cancer cell lines of a wide variety of tissue types, we reveal that ecDNAs have the highest rate of oncogene fusion events of any copy-number alteration. Focusing on the most common ecDNA fusion hotspot, we find that fusion of the 5' end of the long noncoding RNA gene, PVT1-with exon 1 joined to diverse 3' partners-confers increased RNA stability, potentially via an SRSF1-dependent mechanism, and enhances MYC-dependent transcription and cancer cell survival. These results demonstrate that ecDNA fosters genome instability and frequent oncogene fusion formation in cancer.
    Keywords:  PVT1; RNA fusion; RNA stability; SRSF1; cancer; ecDNA; extrachromosomal DNA; oncogene
    DOI:  https://doi.org/10.1016/j.cell.2025.12.009
  15. bioRxiv. 2025 Dec 31. pii: 2025.12.30.686824. [Epub ahead of print]
    NIPBL-mediated 3D genome folding translates enhancer priming into gene activation and safeguards lineage fidelity during embryonic transitions.
    Zhangli Ni, Xiaohui Ma, Stephanie C Do, Lingling Cheng, Rachel A Glenn, Thomas Vierbuchen, Alexandros Pertsinidis.
      Precise gene control by complex regulatory landscapes is fundamental to embryo development, yet the instructive role of 3D genome architecture remains controversial. While acute cohesin depletion completely disrupts genome folding, it yields modest transcriptional impacts, but these findings are often confounded by cohesin's essential roles in cell division and proliferation. Here, we resolve this discrepancy by decoupling architectural functions from cell-cycle roles using an acute NIPBL degron system. By integrating single-gene imaging with single-cell and bulk multi-omics during mouse pluripotency transitions and germ-layer specification, we show that NIPBL-mediated cohesin function is required for proper de novo activation of lineage-specifying genes. Mechanistically, NIPBL translates epigenetic priming into transcriptional outputs by physically bringing distal enhancers and target promoters into proximity. We further uncover a dual regulatory role: an acute requirement for establishing new enhancer-promoter interactions during cell state transitions and a long-term role in safeguarding transcriptional fidelity by preventing ectopic gene de-repression. Our findings demonstrate that NIPBL/cohesin-orchestrated genome folding facilitates the faithful execution of developmental gene expression programs.
    Highlights: Acute NIPBL depletion decouples the architectural functions of cohesin from its essential roles in chromosome segregation and cell cycle progression.NIPBL-mediated loop extrusion is required to translate the epigenetic priming of distal enhancers into de novo gene activation during embryonic state transitions.NIPBL is a "rate-limiting physical relay" required to bring distal enhancers and target promoters into proximity to initiate transcription.3D genome architecture serves a dual role: enabling acute enhancer-promoter communication and safeguarding long-term lineage fidelity by preventing ectopic gene de-repression.
    DOI:  https://doi.org/10.64898/2025.12.30.686824
  16. Cell Rep. 2026 Jan 06. pii: S2211-1247(25)01561-X. [Epub ahead of print]45(1): 116789
    PARG regulates the proteasomal degradation of TARG1.
    Joséphine Groslambert, Sara C Buch-Larsen, Ivo A Hendriks, Robert Kurzbauer, Jonas D Elsborg, Chatrin Chatrin, Thomas Agnew, Callum Henfrey, Michael Tellier, Evgeniia Prokhorova, Song My Hoang, Jonathan Barosso-Gonzalez, Roderick J O'Sullivan, Tim Clausen, Michael L Nielsen, Ivan Ahel.
      ADP-ribosylation (ADPr) is a reversible modification of macromolecules critical for the regulation of genome stability, stress responses, and proteostasis. While the roles of ADPr transferases such as PARP1/2 and TNKS1/2 are well established, the functions and regulatory mechanisms of ADPr hydrolases are still poorly understood. Here, we identify a function of the poly(ADP-ribose) glycohydrolase PARG in regulating protein degradation. Using quantitative proteomics, we show that PARG inhibition depletes protein levels of the mono-ADPr hydrolase TARG1. We demonstrate that this TARG1 depletion is both PAR and proteasome dependent and identify the E3 ubiquitin ligases HUWE1 and TRIP12 as mediators of this process. Our findings establish TARG1 as a substrate of PAR-dependent protein degradation and uncover a PARG-dependent mechanism controlling its stability. This work highlights an interplay between the two ADP-ribosyl hydrolases, with implications for the refinement of PARG-targeted therapeutic strategies.
    Keywords:  ADP-ribosylation; CP: molecular biology; DNA damage; PARP; proteasomal degradation; ubiquitylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116789
  17. Nature. 2026 Jan 07.
    Nutrient requirements of organ-specific metastasis in breast cancer.
    Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Diya L Ramesh, Sophie E Honeder, Ashwin S Kumar, Michelle Wu, Jacob A Hansen, Anna Shevzov-Zebrun, Edrees H Rashan, Kian M Eghbalian, Sharanya Sivanand, Anna M Barbeau, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E Trojan, Millenia Waite, Tenzin Kunchok, Mayu A Nakano, Florian Gourgue, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.
      Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
    DOI:  https://doi.org/10.1038/s41586-025-09898-9
  18. Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01016-0. [Epub ahead of print]
    ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis.
    Siyuan Jiang, Jinghan Sun, Ya Gao, Haifeng Zhang, Ying He, Yibi Zhang, Zhiyuan Xu, Shuwen Cheng, Hong Yan, Liqiang Duan, Peng Xu, Qinong Ye, Shan Gao.
      The view of mRNA function as a translational template is being challenged beyond translation. However, how these non-canonical mRNAs function independently of their coding protein remains largely unexplored. Here, we found that intercellular adhesion molecule 1 (ICAM1) depletion via CRISPR-Cas9 protein knockout and shRNA-mediated RNA knockdown produces opposite effects on cell proliferation in human cells, which is validated by overexpression of mutated coding ICAM1 mRNA and ICAM1 coding sequence (CDS). Mechanistically, cis-antisense transcripts of ICAM1/ICAM1-AS form a double-stranded RNA (dsRNA), which entraps the interleukin enhancer binding factor 2 (ILF2)/ILF3 complex to inhibit DNA binding in a length-dependent manner, thus suppressing EIF4E transcription and global protein synthesis. Clinical analysis highlights the coordinated downregulation of ICAM1/ICAM1-AS, independent of highly expressed ICAM1 protein in lung cancer. In conclusion, this study reveals a role for ICAM1 mRNA in regulating cellular transcription via the dsRNA-ILF2/3 axis. Our findings challenge the phenotype explanation of gene silencing between RNA knockdown and protein knockout and underscore independent mRNA functions.
    Keywords:  ICAM1; ILF2/ILF3 complex; dsRNA; lncRNAs; non-canonical mRNAs function; translation
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.017
  19. Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01023-8. [Epub ahead of print]
    IFI16 senses and protects stalled replication forks.
    Amelia Gamble, Thomas A Ward, Otto P G Wheeler, Jessica P Morris, Caryl M Jones, Laura G Bennett, Ellen G Vernon, Vithursha Thanendran, Ilaria Ceppi, Swagata Halder, Damiano Borrello, Thomas D J Walker, Jahnavi Rajan, Hadil Suleiman, Daniel Harrison, Manal Ashetiwi, Gillian Dunphy, Lucy H Jackson-Jones, Petr Cejka, Leonie Unterholzner, Christopher J Staples.
      Replication stress is a key driver of DNA damage and genome instability. Here, we report that replication stress induces an inflammatory response in the absence of DNA damage. The DNA-sensing factor interferon-γ-inducible factor 16 (IFI16) binds nascent DNA at stalled replication forks and signals via the adaptor stimulator of interferon genes (STING) to induce activation of nuclear factor κB (NF-κB) and the production of pro-inflammatory cytokines, independently of the cytosolic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS). Replication stress-induced fork remodeling generates a new DNA end that is vulnerable to degradation by nucleases and is protected by a range of factors, including the tumor suppressors BRCA1 and BRCA2. IFI16 acts directly at stalled replication forks to protect nascent DNA from degradation by the nucleases MRE11, EXO1, and DNA2. Furthermore, IFI16 is required for the interferon-mediated rescue of fork protection in BRCA-deficient cells, highlighting the critical role of IFI16 in the crosstalk between innate immunity and fork protection during replication stress.
    Keywords:  BRCA1; BRCA2; DNA sensing; IFI16; IL-6; MRE11; NF-κB; STING; fork protection; inflammation; replication stress; reversed replication forks
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.024
  20. Nat Cell Biol. 2026 Jan 09.
    RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress.
    Tyler H Stanage, Shudong Li, Sandra Segura-Bayona, Aurora I Idilli, Rhona Millar, Graeme Hewitt, Simon J Boulton.
      SLFN11 is epigenetically silenced and confers chemoresistance in half of all cancers. In response to replication stress, SLFN11 triggers translation shutdown and p53-independent apoptosis, but how DNA damage activates SLFN11 remains unclear. Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase-polymerase (PrimPol)-mediated repriming. SLFN11 and the downstream integrated stress response uniquely promote cisplatin-driven apoptosis in PrimPol-deficient cells. We demonstrate that replication protein A (RPA) exhaustion and single-stranded DNA exposure trigger SLFN11 activation and cell death when PrimPol is inactivated. We further identify the USP1-WDR48 deubiquitinase complex as a positive modulator of SLFN11 activation in PrimPol-deficient cells, revealing an addiction to the Fanconi anaemia pathway to resolve cisplatin lesions. Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress.
    DOI:  https://doi.org/10.1038/s41556-025-01852-1
  21. Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2515183123
    Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.
    Janine Sengstack, Jiashun Zheng, Turan Aghayev, Gregor Bieri, Michael Mobaraki, Jue Lin, Changhui Deng, Saul A Villeda, Hao Li.
      Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging-increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.
    Keywords:  Perturb-seq screening; liver aging; rejuvenation; replicative aging
    DOI:  https://doi.org/10.1073/pnas.2515183123
  22. Nat Struct Mol Biol. 2026 Jan 08.
    Redox-driven ADAR1 activation promotes Okazaki fragment maturation and DNA replication integrity.
    Bin Chen, Guangchao Sun, Jake A Kloeber, Huaping Xiao, Yaobin Ouyang, Fei Zhao, Ya Li, Shilin Xu, Sonja Dragojevic, Zheming Wu, Shouhai Zhu, Yiqun Han, Ping Yin, Xinyi Tu, Hongran Qin, Xiang Zhou, Kuntian Luo, Kevin L Peterson, Jinzhou Huang, Taro Hitosugi, Haiming Dai, Min Deng, Robert W Mutter, Zhenkun Lou.
      Okazaki fragment maturation requires efficient removal of RNA primers to form a continuous lagging strand, yet how mismatched primers introduced by error-prone primase are corrected remains unresolved. Here, we show that physiological levels of reactive oxygen species (ROS) initiate a redox-dependent mechanism that drives ADAR1-mediated adenosine-to-inosine (A-to-I) editing. Oxidation triggers ADAR1 dimerization at replication forks, enhancing RNA editing of mismatched primers-particularly those caused by ATP misincorporation on d(T+C)-rich centromeric DNA. This A-to-I editing step facilitates more efficient RNA primer degradation by RNase H2, thereby ensuring proper Okazaki fragment maturation. Disruption of ADAR1 oxidation results in increased unligated Okazaki fragments, single-stranded gaps and double-strand breaks, most prominently at centromeres. These findings reveal a role for ROS in safeguarding lagging-strand synthesis by coupling ADAR1 oxidation-induced A-to-I RNA editing to replication fork stability.
    DOI:  https://doi.org/10.1038/s41594-025-01736-w
  23. Cell Stem Cell. 2026 Jan 08. pii: S1934-5909(25)00449-7. [Epub ahead of print]
    A peripheral glial niche orchestrates the early stages of skin wound healing.
    Salome Stierli, Adrian Salas-Bastos, Sofia Micheli, Isabel Ballwein, Andrea Kelemen, Julia Lehmann, Benjamin Loos, Whitney Shannon Jordaan, Sebastian A Stifter, Myriam Gwerder, Ravidu Nakandalage, Janine Stadler, Melanie Greter, Lukas Sommer.
      Skin repair is a complex, dynamic process involving multiple cell types. Using multiplex imaging, spatial transcriptomics, and single-cell RNA sequencing, we show that peripheral nerves-containing repair glia-form a pro-reparative niche closely interacting with macrophages and proliferating fibroblasts in acute skin wounds. Repair glia function as critical early-stage regulators of wound healing by initiating the inflammatory response through secretion of monocyte chemoattractant proteins, such as CCL2, which recruit monocyte-derived macrophages. Accordingly, depletion of repair glia as well as glia-specific deletion of CCL2 reduces the number of macrophages, leading to impaired fibroblast proliferation and diminished fibroblast-to-myofibroblast transition. These findings identify repair glia as early regulators of the immune response, orchestrating the spatiotemporal progression of wound healing.
    Keywords:  dedifferentiation; macrophage; niche; peripheral glia; plasticity; recruitment; regeneration; skin; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.stem.2025.12.015
  24. bioRxiv. 2025 Dec 22. pii: 2025.12.19.695003. [Epub ahead of print]
    Stress-induced loss of CTCF reveals an alternative, promoter-based mode of cohesin looping.
    J P Flores, Andrea A Perreault, Zack Drum, Chenxi Xu, Doris Cruz Alonso, Gelila Petros, Yijia Wu, Ivana Y Quiroga-Barber, HyunAh Kim, Isha Sahasrabudhe, Justin Demmerle, Gang Greg Wang, Danfeng Cai, Douglas H Phanstiel.
      Cells continually encounter environmental stressors that challenge homeostasis. How three-dimensional (3D) chromatin structure contributes to these stress responses, particularly under hyperosmotic conditions, remains poorly understood. Here, using time-resolved Hi-C, CUT&Tag, auxin-inducible depletion, and RNA-seq, we map 3D chromatin structure, its molecular drivers, and transcriptional outcomes during the hyperosmotic stress response. Within 1 hour of sorbitol treatment, pre-existing loops and domains undergo genome-wide collapse, accompanied by the emergence of several hundred de novo, sorbitol-induced loops that are more punctate, longer-range, and transient. These newly formed loops weaken over time and largely dissipate by 24 hours, coincident with recovery of pre-existing chromatin structure. Loop reorganization is consistent across human cell types and hyperosmotic stimuli. CUT&Tag and degron experiments reveal that sorbitol-induced loops require cohesin but not CTCF. Newly formed loop anchors are enriched at active promoters containing SP and KLF family motifs. Genes located at these anchors show little immediate transcriptional change but are activated several hours after loop formation, consistent with loops functioning upstream of gene activation. Together, our findings show that hyperosmotic stress triggers a rapid, reversible, and CTCF-independent reorganization of 3D chromatin interactions that helps coordinate transcriptional adaptation.
    DOI:  https://doi.org/10.64898/2025.12.19.695003
  25. bioRxiv. 2025 Dec 25. pii: 2025.12.23.696255. [Epub ahead of print]
    Mammalian metaphase kinetochores are elastic and require condensin for robust structure and function.
    Vanna M Tran, Jinghui Tao, Caleb J Rux, David Gomez Siu, Miquel Rosas-Salvans, Sophie Dumont.
      The mammalian kinetochore connects chromosomes to dynamic spindle microtubules. To remain attached, it must maintain its structural integrity under force, but to what extent and how it does so remain unclear. Under spindle forces, we find using super resolution microscopy that inner (CENP-A) and outer (Hec1) metaphase kinetochores undergo correlated, large-scale (1 μm) deformations along the force axis, suggesting dynamic, relative sliding of parallel protein linkages. Kinetochore shape changes can be asymmetric, with centromere-facing "tails" correlating with erroneous attachment geometries. Applying microneedle pulling forces, we demonstrate that kinetochores are elastic, stretching under force and relaxing in seconds afterwards. Finally, we show that SMC2 depletion results in more variable kinetochore deformations, despite maintained elasticity, and in reduced microtubule attachment stability. Thus, the kinetochore is structurally highly dynamic and requires a stable centromere base to maintain its structure and function under force. We propose a model whereby individual protein linkages are stiff yet global kinetochore structure flexible to accommodate different attachment geometries and forces while maintaining function.
    DOI:  https://doi.org/10.64898/2025.12.23.696255
  26. Science. 2026 Jan 08. eady5532
    Mitochondrial control of fuel switching via carnitine biosynthesis.
    Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Rose Witte, Jin-Seon Yook, Anthony R P Verkerke, Alexander S Banks, Sheng Hui, Lijun Sun, Shingo Kajimura.
      Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.
    DOI:  https://doi.org/10.1126/science.ady5532
  27. Mol Cell. 2026 Jan 08. pii: S1097-2765(25)00980-3. [Epub ahead of print]86(1): 135-149.e9
    Membrane-protein-mediated phase separation orchestrates organelle contact sites.
    Christian Hoffmann, Takahiro Nagao, Taka A Tsunoyama, Johannes Vincent Tromm, Chinyere Logan, Koki Nakamura, Han Wang, Frans Bianchi, Geert van den Bogaart, Akihiro Kusumi, Yusuke Hirabayashi, Dragomir Milovanovic.
      Mitochondria and the endoplasmic reticulum (ER) contain large areas that are in close proximity. Yet the mechanism of how these inter-organellar adhesions are formed remains elusive. Tight functional connections, termed "membrane contact sites," assemble at these areas and are essential for exchanging metabolites and lipids between the organelles. Recently, the ER-resident protein PDZ domain-containing protein 8 (PDZD8) was identified as a tether between the ER and mitochondria or late endosomes/lysosomes. Here, we show that PDZD8 can undergo phase separation via its intrinsically disordered region (IDR). Endogenously labeled PDZD8 forms condensates on membranes both in vitro and in mammalian cells. Electron microscopy analyses indicate that the expression of full-length PDZD8 rescues the decrease in inter-organelle contacts in PDZD8 knockout cells but not PDZD8 lacking its IDR. Together, this study identifies that PDZD8 condensates at the lipid interfaces act as an adhesive framework that stitches together the neighboring organelles and supports the structural and functional integrity of inter-organelle communication.
    Keywords:  PDZD8; biomolecular condensates; endoplasmic reticulum; liquid-liquid phase separation; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.006
  28. Neuron. 2026 Jan 02. pii: S0896-6273(25)00856-6. [Epub ahead of print]
    Oligodendrocyte mechanotransduction channel TMEM63A regulates myelin sheath geometry.
    Ram R Dereddi, Minou Djannatian, Frederic Fiore, Darshana Kalita, Clement Verkest, Felipe Bodaleo Torres, Wiebke Möbius, Babak Khodaie, Torben Ruhwedel, Khaleel Alhalaseh, Martina Schifferer, Angela Wirth, Anthony Hill, Roger Ottenheijm, Annarita Patrizi, Oliver Kann, Stefan G Lechner, Marc Freichel, Amit Agarwal.
      Oligodendrocytes, the myelinating cells of the central nervous system, precisely sculpt their insulating membranes to match axon size, ensuring fine-tuned action potential propagation. How oligodendrocytes estimate axon caliber to adapt myelin sheath geometry is unknown. The biochemical measure of axonal size provided by neuregulin 1 for Schwann cells is dispensable in oligodendrocytes, and we reasoned that biophysical cues might instead be required. By combining transcriptomics, in vivo optical imaging, and electron microscopy in mouse and zebrafish models, we identified TMEM63A as a key mechanosensitive channel in oligodendrocytes. TMEM63A enabled oligodendrocytes to sense membrane stretch and translate it into Ca2+ signals. In the absence of TMEM63A, developmental myelination was severely impaired with shorter and thinner myelin sheaths on large-diameter axons, ectopic myelination of very small-diameter axons, and increased sheath retractions. We propose MYO5A-dependent Mbp mRNA targeting to the nascent myelin sheaths as a mechanism linking stretch-activated Ca2+ signaling to myelin formation and sheath geometry refinement.
    Keywords:  HLD19; MBP transport; TMEM63A; axon-glia interactions; calcium signaling; mechanical forces; mechanotransduction channels; myelination; myosin5a; oligodendrocyte; transient infantile hypomyelinating leukodystrophy-19
    DOI:  https://doi.org/10.1016/j.neuron.2025.11.009
  29. EMBO J. 2026 Jan 08.
    Dual pathways via CENP-C and Mis18C recruit HJURP for CENP-A deposition into vertebrate centromeres.
    Tetsuya Hori, Yutaka Mahana, Mariko Ariyoshi, Tatsuo Fukagawa.
      Centromere position is specified and maintained by sequence-independent epigenetic mechanisms in vertebrate cells, with the incorporation of the centromere-specific histone H3 variant CENP-A into chromatin being a key event for centromere specification. Although many models for CENP-A incorporation have been proposed, much remains unknown. In this study, we reveal that the CENP-A chaperone HJURP directly binds to the C-terminal domain of chicken CENP-C in vitro and that this interaction is essential for new CENP-A incorporation in chicken DT40 cells. While existing models have suggested that HJURP is recruited by the Mis18 complex (Mis18C), here, we propose that CENP-C and Mis18C provide dual recruitment pathways for HJURP localization to centromeres in DT40 cells. We demonstrate that both HJURP localization and new CENP-A incorporation are completely abolished in Mis18C knockout cells expressing an HJURP mutant lacking CENP-C binding ability. Furthermore, co-immunoprecipitation experiments reveal that CENP-C, HJURP and Mis18C form a tight association in the chromatin fraction. These two pathways are critical for robust CENP-A incorporation to maintain centromere position in vertebrate cells.
    Keywords:  CENP-A; CENP-C; Centromere; HJURP; Mis18 Complex
    DOI:  https://doi.org/10.1038/s44318-025-00674-z
  30. Circulation. 2026 Jan 06.
    Inhibition of Annexin A2 Facilitates PHB2-Mediated Mitophagy in Cardiomyocytes to Alleviate Cardiac Injury and Remodeling After Infarction.
    Ke-Qiong Deng, Zhendong Xu, Qiong-Xin Wang, Huan-Huan Cai, Di Fan, Qingqing Wu, Xiao-Jing Zhang, Peng Zhang, Zhi-Gang She, Xingguo Liu, Xianqing Li, Zhibing Lu.
       BACKGROUND: Mitophagy is critically involved in cardiac injury and repair after myocardial infarction (MI), whereas the annexin A family plays an important role in mitophagy. However, the intrinsic molecular underpinnings that orchestrate the homeostasis of mitophagy in the infarcted heart remain to be fully characterized. Here, we aimed to evaluate the role of ANXA2 (annexin A2) in cardiac mitophagy in response to MI.
    METHODS: Transcriptome analyses were conducted to identify differentially expressed genes and enriched pathways. Mitophagy, mitochondrial function, and cardiac injury and remodeling were analyzed in MI mice and neonatal rat ventricular myocytes with cardiomyocyte-specific ANXA2 knockdown or overexpression, as well as in models with ANXA2 knockdown combined with PHB2 (prohibitin 2) silencing. Immunoprecipitation, mass spectrometry, and glutathione S-transferase pull-down assays were used to identify the interacting proteins of ANXA2.
    RESULTS: We showed that ANXA2 was highly expressed in murine and human ischemic failing hearts, whereas increased circulating ANXA2 positively correlated with cardiac injury in patients with acute MI. Moreover, cardiomyocyte-specific ANXA2 depletion averted cardiac mitophagy inactivation, oxidative stress, cell death, and inflammatory cell infiltration, leading to significant improvements in infarct size, heart function, and cardiac remodeling after MI. Conversely, ANXA2 overexpression in cardiomyocytes suppressed mitophagy to exacerbate cardiac injury and deteriorate heart failure after MI. Moreover, ANXA2 silencing and overexpression, respectively, in neonatal rat ventricular myocytes under hypoxia in vitro recapitulated the in vivo findings on mitochondrial function and cell death. Mechanistically, we found that ANXA2 directly interacted with the mitophagy receptor PHB2 to competitively block the binding of LC3B with PHB2 and promote PHB2 proteasomal degradation through K48-linked polyubiquitination mediated by the E3 ligase TRIM29, resulting in mitophagy inhibition under hypoxia. Consequently, PHB2 knockdown abrogated the protective effects of ANXA2 deficiency on mitochondrial function, oxidative stress, and cell viability in stressed myocytes in vitro, as well as on heart function and remodeling under MI in vivo.
    CONCLUSIONS: These findings highlight the significance of ANXA2 inhibition as a molecular brake on mitophagy inactivation in cardiomyocytes under MI and uncover an ANXA2-mediated posttranslational mechanism essential for maintaining mitochondrial homeostasis and alleviating heart failure after MI.
    Keywords:  cardiomyocyte; mitochondrial function; mitophagy; myocardial infarction; proteasomal degradation
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.077780
  31. Nat Commun. 2026 Jan 03.
    Oxidative stress and GPX2 control pancreatic vs. non-pancreatic cell fate in human endoderm.
    Joanna Szpotkowska, Wojciech J Szlachcic, Katarzyna Blaszczyk, Maja Baginska, Magdalena Socha, Malgorzata Borowiak.
      Cell fate decisions in human endoderm development are tightly regulated, yet the role of metabolic products remains elusive. The endodermal posterior foregut gives rise to pancreas, liver, and intestine. Here, we identify Glutathione Peroxidase 2 as a critical regulator of human posterior foregut differentiation, revealing oxidative stress as a key determinant of pancreatic versus non-pancreatic cell fate. Cells lacking Glutathione Peroxidase 2 under pancreas-promoting conditions differentiate also into hepatic-like progenitors. Through bulk and single-cell transcriptomics, chromatin accessibility profiling, and functional studies, we reveal that Glutathione Peroxidase 2 orchestrates lineage commitment by regulating key transcription factors, leading to emergence of multilineage liver and intestinal progenitors. Mechanistically, Glutathione Peroxidase 2 deficiency triggers extracellular matrix remodeling, activating bone morphogenetic protein signaling and skewing differentiation from the pancreatic lineage. Manipulating oxidative stress recapitulates or rescues Glutathione Peroxidase 2 loss effects, establishing oxidative stress as a gatekeeper of pancreatic fate. Controlling oxidative stress during in vitro differentiation could advance regenerative medicine applications.
    DOI:  https://doi.org/10.1038/s41467-025-68145-x
  32. Nat Commun. 2026 Jan 03. 17(1): 132
    CUL4A-DDB1-DCAF10 is an N-recognin for N-terminally acetylated Src kinases.
    Nora Kremer, Franziska Mueller, Hang Nguyen, Louisa Schulz, Tanja Popp, Elena Artes, Julian Wolters, Michael Renner, Ingrid Vetter, Stefano Maffini, Maria S Robles, Andrea Musacchio, Tanja Bange.
      Co-translational N-terminal modifications such as methionine excision, acetylation, and myristoylation govern protein stability, localization, and folding. Disruption can expose N-terminal degrons that trigger ubiquitin-mediated degradation, safeguarding the proteome. N-terminal acetylation usually protects proteins from degradation, but can also promote it through the Ac/N-degron pathway. Src-family kinases (SFKs), signaling enzymes implicated in tumorigenesis, require N-terminal myristoylation for function. Using peptide pull-downs, mass spectrometry, and AlphaFold 3 predictions, we identify DCAF10 as the E3 ligase substrate receptor for alternatively N-terminally acetylated SFKs. Combining siRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of endogenous Lyn with inducible Lyn-GFP variants confirms that DCAF10 regulates SFK levels by recognizing an N-terminal acetylated glycine residue. In vitro, a CUL4A-DDB1-DCAF10 complex ubiquitinates N-terminally acetylated SFKs. Thus, we define a novel N-degron pathway that monitors replacement of myristoylation by acetylation and activates degradation of SFKs upon acetylation. This mechanism may extend to other N-terminally myristoylated proteins beyond SFKs.
    DOI:  https://doi.org/10.1038/s41467-025-68074-9
  33. Sci Transl Med. 2026 Jan 07. 18(831): eadx2876
    Extracellular BRICK1 drives heart repair after myocardial infarction in mice.
    Felix Polten, Mircea-Andrei Sandu, Jan Faix, Jan Hegermann, Nils Kriedemann, Robert Zweigerdt, Thomas Thum, Johann Bauersachs, Hans W Niessen, Andrew L Koenig, Kory J Lavine, Andreas Pich, Yong Wang, Marc R Reboll, Mortimer Korf-Klingebiel, Kai C Wollert.
      Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell-endothelial cell interactions. Here, we identify the 75-amino acid microprotein BRICK1 (BRK1) as an indispensable driver of postinfarction angiogenesis in a mouse model of reperfused myocardial infarction. We show that BRK1 is preferentially expressed by myeloid cells and translocates to the extracellular space after myocardial infarction in mice and humans. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We find that BRK1 is not actively secreted but released during myeloid cell death. Cre-loxP-driven myeloid cell-selective genetic deletion of Brk1 or antibody-mediated neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Conversely, treatment with recombinant BRK1 preserved heart function in infarcted mice. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase Ras-related protein Rap-1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic factor linking myeloid cell death to ischemic tissue repair, potentially enabling a protein-based therapy for myocardial infarction.
    DOI:  https://doi.org/10.1126/scitranslmed.adx2876
  34. J Cell Biol. 2026 Mar 02. pii: e202407146. [Epub ahead of print]225(3):
    HP1 isoforms direct repair pathway choice in response to heterochromatin double-strand breaks.
    Darshika Bohra, Aprotim Mazumder.
      Double-strand breaks (DSBs) threaten genomic stability and need immediate attention from DNA damage response (DDR) machinery involved in homologous recombination (HR) or nonhomologous end joining (NHEJ). DDR in heterochromatin is challenging owing to the distinct chromatin organization. Heterochromatin protein 1 (HP1) isoforms are central to heterochromatin structure and have been implicated in DDR. Mammalian HP1 has three isoforms, HP1α, HP1β, and HP1γ, which possess significant homology and yet have distinct functions. HP1α is the only isoform known to undergo liquid-liquid phase separation mediated by phosphorylation on the N-terminal extension (NTE). We show that the minute-scale dynamics of HP1α and HP1β differ dramatically and differentially influence the recruitment of HR vs. NHEJ factors at sites of laser-induced clustered DSBs. Perturbing HP1α phosphorylation impairs HR factor recruitment and reduces HR efficiency. Our study provides a potential link between phase separation and DDR-centric roles of HP1α and hints at spatial partitioning of repair pathways in response to damage in heterochromatin.
    DOI:  https://doi.org/10.1083/jcb.202407146
  35. J Cell Biol. 2026 Mar 02. pii: e202504139. [Epub ahead of print]225(3):
    The adipose tissue has an apical-basal polarity required for Col IV-dependent cell-cell adhesion.
    Jameela Almasoud, Cyril Andrieu, Bren Hunyi Lee, Anna Franz.
      In epithelia, the apical-basal polarity machinery positions E-cadherin-based adherens junctions at the apical-lateral border to mediate cell-cell adhesion. The Drosophila adipose tissue, the fat body, forms a monolayer in which integrin-binding to collagen IV intercellular concentrations mediates cell-cell adhesion. How these atypical adhesion complexes form is unknown. Here we show that the fat body has apical-basal polarity, with aPKC, Crumbs, and Par-6 on the opposite side of Lgl and Dlg. Collagen IV, Laminin, Perlecan, and Nidogen are abundant in the basal basement membrane, while collagen IV predominates in the apical basement membrane. Crumbs, aPKC, Scribble, and Lgl knockdown in the fat body lead to cell-cell adhesion defects. Moreover, aPKC is essential for the formation of collagen IV intercellular concentrations. We further show that during fat body remodeling, Ecdysone regulates the loss of apical-basal polarity and collagen IV intercellular concentrations to induce cell-cell dissociation and swimming migration. Our work hence uncovers a novel role for apical-basal polarity in the Drosophila adipose tissue in regulating cell-cell adhesion via collagen IV intercellular concentrations.
    DOI:  https://doi.org/10.1083/jcb.202504139
  36. J Cell Biol. 2026 Apr 06. pii: e202511114. [Epub ahead of print]225(4):
    Condensin II collaborates with cohesin to establish and maintain interphase chromosome territories.
    Takao Ono, Masatoshi Takagi, Hideyuki Tanabe, Tomoko Fujita, Noriko Saitoh, Akatsuki Kimura, Tatsuya Hirano.
      Despite the well-established role of condensin II in mitotic chromosome assembly, its function in interphase chromosome organization remains poorly understood. Here, we applied multiscale FISH techniques to human cell lines engineered for single or double depletion of condensin II and cohesin and examined their functional collaboration at two distinct stages of the cell cycle. Our results demonstrate that a functional interplay between condensin II and cohesin during the mitosis-to-G1 transition is critical for establishing chromosome territories (CTs) in the newly assembling nucleus. During the G2 phase, condensin II and cohesin cooperate to maintain global CT morphology, although they act at different genomic scales. Strikingly, double depletion of both complexes causes CTs to collapse and accumulate abnormally at the nucleolar periphery. Based on these findings, we will discuss how the condensin and cohesin complexes act in an orderly and cooperative manner to orchestrate chromatin dynamics across genomic scales, thereby supporting higher-order chromosome organization throughout the cell cycle.
    DOI:  https://doi.org/10.1083/jcb.202511114
  37. J Cell Biol. 2026 Mar 02. pii: e202503046. [Epub ahead of print]225(3):
    Keratin 15 promotes a progenitor cell state in basal keratinocytes of skin epidermis.
    Catherine J Redmond, Sarah N Steiner, Erez Cohen, Craig N Johnson, Nurhan Özlü, Pierre A Coulombe.
      The type I intermediate filament proteins keratin 14 (K14) and keratin 15 (K15) are common to all complex epithelia. K14 is highly expressed by progenitor keratinocytes, in which it provides essential mechanical integrity and gates keratinocyte entry into differentiation by sequestering YAP1, a transcriptional effector of Hippo signaling, to the cytoplasm. K15 has long been used as a marker of hair bulge stem cells, though its specific role in skin epithelia is unknown. Here, we show that the lack of two biochemical determinants, a cysteine residue within the stutter motif of the central rod domain and a 14-3-3 binding site in the N-terminal head domain, renders K15 unable to effectively sequester YAP1 in the cytoplasm like K14 does. We combine insight obtained from cell culture and transgenic mouse models with computational analyses of transcriptomics data and propose a model in which a higher K15:K14 ratio promotes a progenitor state and antagonizes differentiation in keratinocytes of the epidermis.
    DOI:  https://doi.org/10.1083/jcb.202503046
  38. Sci Adv. 2026 Jan 09. 12(2): eadz7607
    Friction-driven scission: How nonlocal mechanisms contribute to membrane fission across domains of life.
    Ane Landajuela, Carolina Gomis Perez, Patricia Bassereau, Andrew Callan-Jones, Erdem Karatekin.
      Membrane fission is an energy-consuming process, critical for all domains of life. Prototypical fission machineries use local energy input such as nucleoside triphosphate hydrolysis to constrict and cut membranes. However, some membrane fission reactions paradoxically rely on protein scaffolds that by themselves stabilize rather than cut membranes. It turns out these proteins do not work alone; they use nonlocal energy input that generates a membrane tension gradient. Such a gradient mobilizes membrane flow that in turn tends to relax the membrane tension gradient. By interfering with membrane flow, the protein scaffold causes the membrane tension to increase unchecked to the point of mechanical failure, membrane fission. This friction-driven scission (FDS) mechanism is generic, conserved from bacteria to humans, and only requires two ingredients: a membrane tension generating process and a protein scaffold that hinders the associated membrane flow. Because both are often present in cells, it is likely that FDS contributes to membrane fission more frequently than previously appreciated.
    DOI:  https://doi.org/10.1126/sciadv.adz7607
  39. Cell. 2026 Jan 05. pii: S0092-8674(25)01378-9. [Epub ahead of print]
    Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors.
    Jiao Liu, Xiutao Cai, Junhao Lin, Zhenhui Zhang, Qile Zhou, Xiao Zhang, Lifang Ma, Yayou Miao, Ruoxi Zhang, Chunhua Yu, Yingyi Yang, Yangchun Xie, Rui Kang, Daniel J Klionsky, Peng Liu, Guido Kroemer, Daolin Tang, Jiayi Wang.
      Understanding the immunogenic properties of different forms of cell death is critical for rationalized antineoplastic therapeutic development. Here, we identify a regulatory axis that suppresses the immunogenicity of ferroptosis. During ferroptosis, but not apoptosis, cuproptosis, or necroptosis, cancer cells release glutathione peroxidase 4 (GPX4), which binds to zona pellucida glycoprotein 3 (ZP3) on the surface of dendritic cells (DCs), activates the 3',5'-cyclic adenosine monophosphate (cAMP)-protein kinase AMP-activated (PRKA) signaling cascade, inhibits glycolysis, and impairs maturation and activation of DCs, leading to a T cell priming defect. Disrupting the interaction between GPX4 and ZP3 restores DC metabolic activity and enhances antitumor immunity. In preclinical models, blockade of this pathway improves cancer immunosurveillance and potentiates cytotoxic T cell responses when combined with chemotherapy, immunochemotherapy, or radiotherapy. Clinically, high ZP3 expression predicts poor prognosis across multiple solid tumor types, while increased circulating GPX4 levels and ZP3 expression in DCs correlate with resistance to first-line therapies. These findings reveal an immunosuppressive danger signal that limits tumor immunity.
    Keywords:  cancer therapy; cell death; immunogenicity; oxidative stress; zona pellucida family
    DOI:  https://doi.org/10.1016/j.cell.2025.12.002
  40. Nat Cell Biol. 2026 Jan 06.
    Biological clocks keep a watch on mitosis.
    Colin Richard Gliech, Andrew Jon Holland.
      Accurate chromosome segregation is vital for organismal development and homeostasis, with errors in this process strongly associated with tumourigenesis. A network of safeguard clocks preserves mitotic fidelity by detecting and eliminating cells dividing outside the stereotyped duration of successful mitosis. This Perspective examines recent advances in our understanding of mitotic timing mechanisms, presents emerging evidence for novel mitotic clocks and proposes a conceptual framework for how cells integrate temporal cues to preserve genomic integrity.
    DOI:  https://doi.org/10.1038/s41556-025-01784-w
  41. Nat Commun. 2026 Jan 08.
    Dynamins maintain nuclear envelope homeostasis and genome stability.
    Célia Aveleira, Thibaud Martial, Loïc Carrique, Rita Gaspar, Ana Caulino-Rocha, Izaak Myatt, Franz Wendler, Pauline Lascaux, Misha Le Claire, James Bancroft, Carl Smythe, Kristijan Ramadan, Nuno Raimundo, Ira Milosevic.
      The nuclear envelope is a protective barrier for the genome and a mechanotransduction interface between cytoplasm and nucleus, whose malfunction disrupts nucleocytoplasmic transport, compromises DNA repair, accelerates telomere shortening, and promotes genomic instability. Mechanisms governing nuclear envelope remodeling and maintenance in interphase and post-mitotic cells remain poorly understood. Here, we report a role for dynamins, a family of essential brain-enriched membrane- and microtubule-binding GTPases, in preserving nuclear envelope and genomic homeostasis. Cells lacking dynamins exhibit nuclear envelope dysmorphisms, including buds with long narrow necks where damaged DNA frequently accumulates. These cells also show impaired autophagic clearance, reduced levels of key DNA repair proteins, and aberrant microtubules. Nocodazole treatment restores nuclear morphology and reduces DNA damage. Collectively, the data reveal that dynamins promote nuclear envelope homeostasis and removal of damaged DNA via their GTPase activity and interaction with microtubules, providing insights into mechanisms that uphold genome stability and counteract aging-related pathologies.
    DOI:  https://doi.org/10.1038/s41467-025-68130-4
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒19 at 0:55.