bims-ginsta 2026-03-01 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–03–01
forty-four papers selected by
Jinrong Hu, National University of Singapore

THAP1 is a maternal effect factor required for the first cell cycle via Rrm1 in early mouse embryos.
Three-dimensional genome reorganization foreshadows zygotic genome activation in Drosophila.
Class-I myosin responds to changes in membrane tension during clathrin-mediated endocytosis in human induced pluripotent stem cells.
LBR and LAP2 mediate heterochromatin tethering to the nuclear periphery to preserve genome homeostasis.
Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
A non-transcriptional mitotic function of POU/Oct factors ensures spindle assembly and chromosome segregation.
Aspartate availability drives differential engagement of the malate-aspartate shuttle.
Nuclear speckles enable processing of RNA from GC-rich isochores.
The Nemp1-Nesprin complex mediates cellular responses to matrix mechanics.
IRES-cargo interplay structurally modulates circular RNA translation.
Developmentally programmed nuclear pore complex replacement enables oocyte specification.
Transposable element-gene chimera cartography, origination and role in enhancing transcriptome plasticity.
Cell enlargement drives aging-associated proteome remodeling and shortens replicative lifespan.
Single-cell transcriptomics reveals hair growth retardation mediated by aberrant connective tissue sheath contraction in male androgenetic alopecia.
Nucleosome spacing regulates linker methylation by DNMT3A2/3B3.
Human hippocampal neurogenesis in adulthood, ageing and Alzheimer's disease.
Two δ-catenins, plakophilin 4 and p120, promote formation of distinct types of adherens junctions.
Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.
Intercellular Communication via Mitotic Nanotubes is Influenced by Connexin-43 Trafficking and Actin Remodeling.
Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity.
Activation of IRF3 in cardiomyocytes impairs mitochondrial oxidative function through PGC-1α inhibition and drives heart failure.
α-Satellite RNA marks the perinucleolar compartment and represses ribosomal RNA expression in naive human embryonic stem cells.
Reconstitution of sex determination and the testicular niche using mouse pluripotent stem cells.
Reciprocal regulation of fibroblast-macrophage equilibrium governs skin integrity.
Aging-associated mitochondrial circular RNAs.
Collective transitions from orbiting to matrix invasion in three-dimensional multicellular spheroids.
Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.
Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens.
Baculoviruses exploit the mitotic kinase CDK1 to disrupt the nuclear lamina.
Whole-organ and whole-body 3D atlases enable cellome-wide profiling.
ERCC6L2 ensures repair fidelity for staggered-end DNA double-strand breaks.
1,3-Dicarbonyl Rhodamines for Live-Cell Single-Molecule Super-Resolution Imaging.
Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer.
Generation of functionally competent testicular somatic cells from pluripotent stem cells.
iCLAP: an innovative method for integrable co-detection of low-abundance antigens with high-plex immunostaining.
The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.
Nup42 safeguards heat-induced mRNAs from nuclear condensation to support chaperone synthesis.
Nascent transcriptome of embryonic genome activation reveals a regulatory axis linking transcriptional priming to early lineage specification in mouse embryos.
Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis.
The nuclease EXO1 promotes genomic instability by degrading nascent DNA in BRCA-proficient cells.
Hematopoietic stem cell aging promotes TET2 clonal hematopoiesis.
A de novo H3.2K9me2 deposition pathway establishes heterochromatin for suppressing transposon mobilization during fly somatic development.
A lineage-specific selective autophagy receptor module mediates P-body turnover.
Integrator subunit INTS12 links ribotoxic stress to transcription-coupled nucleotide excision repair.

EMBO Rep. 2026 Feb 23.

THAP1 is a maternal effect factor required for the first cell cycle via Rrm1 in early mouse embryos.

Qiang Fan, Xi Wu, Yanna Dang, Lijun Dong, Wenying Wang, Feng Kong, Lijuan Wang, Xukun Lu, Boyang Liu, Shuyan Ji, Wei Xie.

  Maternal effect genes (MEGs) produce factors that accumulate in oocytes and play critical roles in embryo development. Mutations of MEGs are frequently linked to reproductive and congenital disorders. The majority of identified mammalian MEGs encode epigenetic factors and RNA regulators. Here, we identify a MEG encoding the transcription factor Thanatos-associated protein 1 (Thap1). Thap1 is highly expressed in mouse oocytes and early embryos. Oocyte-specific deletion of Thap1 results in delayed progression of mouse embryos from the 1-cell to the 2-cell stage and 1-2-cell arrest, accompanied by defective zygotic genome activation (ZGA) and strongly impaired female fertility. Mechanistically, THAP1 activates a critical subset of genes in oocytes, including Rrm1, which produces ribonucleotide reductase required for generating deoxynucleotide triphosphates (dNTPs). Low-input metabolome profiling across 7 stages during the oocyte-to-embryo transition shows gradual, THAP1-dependent dNTP accumulation that peaks in MII oocytes. Overexpression of Rrm1 in zygotes almost fully restores the 2-cell progression and ZGA in Thap1 maternal-knockout embryos. Our findings identify THAP1 as a key maternal effector critical for the earliest stage of mammalian development.

Keywords:  Cell Cycle; MEG; RRM1; THAP1; dNTP

DOI:  https://doi.org/10.1038/s44319-026-00712-9
Nat Genet. 2026 Feb 24.

Three-dimensional genome reorganization foreshadows zygotic genome activation in Drosophila.

Noura Maziak, Yuchen Zhang, Fabian Groll, Haley E Brown, Alla Madich, Yadwinder Kaur, Melissa M Harrison, Jian Zhou, Juan M Vaquerizas.

How chromatin conformation relates to chromatin state remains a central challenge in genome regulation. Here we present Pico-C, a low-input Micro-C approach that enables high-resolution, temporally resolved three-dimensional genome mapping during early Drosophila embryogenesis. Contrary to a prevailing view of a disorganized genome before zygotic genome activation (ZGA), we uncover a dynamic and ordered emergence of chromatin loops during pre-ZGA nuclear cycles. Spatial autocorrelation analysis points to context-dependent regulatory influences on chromatin. Notably, inhibition of transcriptional elongation has site-specific effects, retaining some early loops while weakening insulation at active promoters, suggesting distinct regulatory dependencies. Machine learning models trained on sequence features identify orthogonal, motif-specific contributions to architecture. Co-depletion of the pioneer factors Zelda and GAF leads to factor-specific perturbations in chromatin architecture, further highlighting a modular regulatory logic in genome establishment. Together, our findings reveal that early genome organization is orchestrated by an interplay of overlapping yet separable regulatory inputs.

DOI: https://doi.org/10.1038/s41588-026-02503-3
Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2532817123

Class-I myosin responds to changes in membrane tension during clathrin-mediated endocytosis in human induced pluripotent stem cells.

Samantha L Smith, Tong Zhan, Wan Li, Henry De Belly, Qing Zhang, Ke Xu, Orion D Weiner, David G Drubin.

  Clathrin-mediated endocytosis (CME) is an essential cellular process that needs to operate efficiently across a wide range of conditions. Internalization of the endocytic site involves forces generated by membrane-bound proteins and Arp2/3-mediated branched actin filament assembly to bend the plasma membrane from flat to omega-shaped. In mammalian CME, the requirement for a branched actin filament network varies depending on cell type and differences in membrane tension. However, how the actin network adapts to changes in load in order to ensure robustness of this process over a range of membrane tensions is not understood. Here, we combine live-cell imaging and superresolution microscopy of genome-edited human induced pluripotent stem cells to investigate the role of the mammalian class-I myosin, Myosin1E (Myo1E), in load adaptation. Under normal conditions, sites that recruit Myo1E are rare and exhibit slow CME dynamics. However, as membrane tension increases and CME dynamics are slowed globally, Myo1E is recruited to more sites, likely to increase actin assembly and motor activity, resulting in increased force generation to rescue stalled sites and promote internalization. Loss of Myo1E results in increased Arp2/3 complex lifetime at CME sites under normal conditions, and at high membrane tension, these sites fail to recruit as many Arp2/3 molecules. We propose that Myo1E is recruited to CME sites that have stalled due to increased membrane tension, where it helps build a more effective branched actin network by generating force through motor activity and recruiting additional Arp2/3 complexes to rescue stalled sites.

Keywords:  Class-I myosin; Clathrin-mediated endocytosis; Myosin1E; membrane tension

DOI:  https://doi.org/10.1073/pnas.2532817123
Nat Cell Biol. 2026 Feb 24.

LBR and LAP2 mediate heterochromatin tethering to the nuclear periphery to preserve genome homeostasis.

Renard Lewis, Virginia Sinigiani, Noura Maziak, Krisztian Koos, Cristiana Bersaglieri, Ivo Zemp, Caroline Ashiono, Constance Ciaudo, Peter Horvath, Juan M Vaquerizas, Raffaella Santoro, Puneet Sharma, Ulrike Kutay.

In most eukaryotic cells, euchromatin is localized in the nuclear interior, whereas heterochromatin is enriched at the nuclear envelope (NE). This conventional chromatin organization is established by heterochromatin tethering to the NE; however, its importance for cellular homeostasis is largely unexplored. One tether is constituted by the lamin B receptor (LBR) in mammals, but the enigmatic nature of other redundant tethers has hampered functional analyses. Here we demonstrate that downregulation of abundant, ubiquitous NE proteins can induce the global detachment of heterochromatin from the NE and its repositioning to the nuclear interior. We identify LBR and lamina-associated polypeptide 2 (LAP2) as key factors for peripheral heterochromatin positioning in differentiated and pluripotent mammalian cells. Their long-term loss leads to changes in three-dimensional chromatin organization and a reduction in repressive epigenetic marks, especially H3K27me3. These changes are associated with massive deregulation of gene expression, activation of antiviral innate immunity, and defects in cell fate determination.

DOI: https://doi.org/10.1038/s41556-025-01822-7
Science. 2026 Feb 26. 391(6788): eadw6273

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.

Ziyu Lu, Zehao Zhang, Zihan Xu, Abdulraouf Abdulraouf, Wei Zhou, Junyue Cao.

To investigate organism-wide cellular alterations and epigenomic dynamics during aging, we constructed a single-cell chromatin accessibility atlas spanning 21 mouse tissues across three age groups and both sexes. We found that around one-quarter of 536 organ-specific cell types and 1828 finer-grained subtypes exhibited considerable age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, indicating systemic signals that coordinate these changes. Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying these shifts. Moreover, ~40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.

DOI: https://doi.org/10.1126/science.adw6273
J Cell Sci. 2026 Feb 23. pii: jcs.264165. [Epub ahead of print]

A non-transcriptional mitotic function of POU/Oct factors ensures spindle assembly and chromosome segregation.

Priya Gohel, Vasilios Tsarouhas, Laveena Kansara, Suresh Sajwan, Ylva Engström.

  POU/Oct transcription factors are critical regulators of cellular processes, including proliferation, cell fate determination, and cancer. Despite their importance, the specific molecular mechanisms by which they influence cell division remain largely unclear. Here, we show that Nub/Pdm1, a Drosophila homolog of human POU2F1/Oct1, is essential for accurate mitotic progression in a non-transcriptional manner. Live imaging and immunostaining in Drosophila syncytial embryos reveal that its depletion leads to disorganized spindles, aberrant chromosome segregation and delayed mitotic progression. Similarly, reduction of POU2F1/Oct1 in live human cells caused disorganized mitotic spindles and spindle collapse. Nub/Pdm1 is enriched within the mitotic spindles and this recruitment is independent of its sequence-specific DNA binding. Instead, it depends on the integrity of spindle microtubules and is regulated by mitosis-related motor proteins, and kinases. Our findings identify both fly Nub/Pdm1 and human Oct1 as important regulators of mitotic progression, acting to maintain spindle stability and proper elongation. The non-transcriptional mitotic role of Nub/Pdm1 reveals a previously unrecognized mechanism of POU/Oct proteins and provides new insight into their potential oncogenic properties.

Keywords:  Cancer; Cell division; Chromosome segregation; Drosophila; Mitosis; Mitotic spindle; Nubbin; Oct1; POU factors

DOI:  https://doi.org/10.1242/jcs.264165
Mol Cell. 2026 Feb 26. pii: S1097-2765(26)00099-7. [Epub ahead of print]

Aspartate availability drives differential engagement of the malate-aspartate shuttle.

Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner, Lydia W S Finley.

  The malate-aspartate shuttle is a major electron shuttle that transfers reducing equivalents from the cytosol to the mitochondria, where they can be safely deposited onto the electron transport chain. Nevertheless, many proliferating cells discard reducing equivalents in the form of lactate, raising the question of what factors limit electron shuttle use. Here, we show that aspartate availability determines engagement of the malate-aspartate shuttle. In proliferating cells, increasing aspartate availability enhances use of the malate-aspartate shuttle and increases metabolism of glucose-derived pyruvate in mitochondria, a process that requires regeneration of oxidized electron carriers in the cytosol. During differentiation, elevated flux through the malate-aspartate shuttle cells enables cells to fuel mitochondrial networks from glucose-derived carbon. Engineering aspartate demand reverses this metabolic signature of differentiated cells. Together, these results demonstrate that cell-state-specific demand for aspartate is sufficient to determine use of the malate-aspartate shuttle and drives changing mitochondrial substrate preferences during differentiation.

Keywords:  GOT1; GOT2; TCA cycle; Warburg effect; aspartate; differentiation; electron shuttles; malate-aspartate shuttle; metabolism; proliferation

DOI:  https://doi.org/10.1016/j.molcel.2026.02.004
Cell. 2026 Feb 25. pii: S0092-8674(26)00098-X. [Epub ahead of print]

Nuclear speckles enable processing of RNA from GC-rich isochores.

Michał Małszycki, Lisa Martina, İbrahim Avşar Ilık, Daniela Salgado Figueroa, Nirmalya Dasgupta, Menşura Feray Çoşar, Keun-Tae Kim, Gil Carraco, Beatrix Fauler, David Meierhofer, Thorsten Mielke, Hiroo Imai, Cantaş Alev, Ferhat Ay, Tuğçe Aktaş.

  Nuclear speckles are conserved, membrane-less organelles linked to various post-transcriptional processes. Here, we examined their roles in human cells by engineered, acute removal of SON and SRRM2, two conserved speckle core components characterized by intrinsically disordered regions (IDRs). Their removal results in a significant downregulation of GC-rich genes with short introns clustered within GC-rich isochores, caused by inefficient and chaotic splicing; in contrast, the expression or splicing of genes outside these isochores remains unaffected. Comparative analysis across eukaryotes, from fungi to mammals, reveals that both GC-rich isochores and speckles are found exclusively in amniotes; moreover, the IDRs of SON have undergone notable expansion in the latter. Together, these findings suggest that the expansion of IDRs in vertebrates facilitated an increase in GC content by creating a condensate essential for splicing the by-products of this process: GC-rich, leveled exon-intron architectures.

Keywords:  RNA splicing; biological condensates; genome evolution; nuclear organization; nuclear speckles

DOI:  https://doi.org/10.1016/j.cell.2026.01.011
Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2521253123

The Nemp1-Nesprin complex mediates cellular responses to matrix mechanics.

Abira Ganguly, Hannah Zmuda, Javier Abello, Danielle Illy, Christopher Walter, Yonit Tsatskis, Nattapon Thanintorn, Ying Zhang, Bilal Ahmad Hakim, Didier Hodzic, Amber N Stratman, Andrea Jurisicova, Amit Pathak, Helen McNeill.

  Nuclear Envelope Membrane Protein 1 (NEMP1) is crucial for metazoan fertility; loss of Nemp1 causes death of primordial oocytes that reside in the mechanically challenging ovarian cortex. Here, we show that softening the ovary rescues oocyte loss and restores fertility in Nemp1 knockout (KO) mice. In cell culture, NEMP1 depletion on stiff substrates leads to death, while cells remain viable on soft substrates. We further show that NEMP1 regulates YAP nuclear translocation, essential for mechanotransduction. Mechanistically, Nemp1-depleted cells on stiff substrates or subjected to stretching exhibit reduced nuclear YAP localization, and expressing nuclear YAP5SA restores cell viability. Loss of NEMP1 disrupts actin organization. Inducing actin polymerization partially rescues nuclear YAP, indicating a role for F-actin in NEMP1 mediated mechanotransduction. NEMP1 forms a complex with NESPRIN's Klarsicht, Anchorage (ANC)-1, Syne Homology (KASH) domain, strengthening the actin cytoskeleton to withstand mechanical forces, independent of SUN proteins. Thus, the Nemp1-Nesprin complex supports a mechanosensitive pathway parallel to the LINC complex, enabling cellular response to mechanical stress in vitro and in vivo.

Keywords:  KASH domain; Nemp1; YAP nuclear translocation; cellular responses to mechanical stress; nuclear mechanotransduction

DOI:  https://doi.org/10.1073/pnas.2521253123
Cell Res. 2026 Feb 26.

IRES-cargo interplay structurally modulates circular RNA translation.

Youkui Huang, Yao-Qi Chen, Si-Yu Lou, Xiang Gao, Yu-Xin Liu, Yu-Lu Zhang, Fang Nan, Ling-Ling Chen, Li Yang.

DOI: https://doi.org/10.1038/s41422-026-01233-9
bioRxiv. 2026 Feb 16. pii: 2026.02.13.705775. [Epub ahead of print]

Developmentally programmed nuclear pore complex replacement enables oocyte specification.

Shruti Venkat, Tram Nguyen, Cecilia Blangini, Michelle Pollak, Karen Schindler, Maya Capelson, Prashanth Rangan.

Oocytes endow embryos with molecular machinery essential for development, but not all maternal components are inherited indiscriminately. In Drosophila, surveillance pathways eliminate defective mitochondria and aberrant RNAs from the maternal pool. Whether stable nuclear structures, like nuclear pore complexes (NPCs), are similarly curated remains unknown. Here, we uncover a developmentally programmed NPC turnover pathway that renews NPCs during oocyte specification. NPC levels decline through a combination of passive dilution, driven by deferred nucleoporin expression, and active degradation mediated by the ESCRT-III/Vps4 pathway. This clearance is counterbalanced by subsequent de novo NPC synthesis. Failure to turn over NPCs results in aberrantly persistent germ cell gene expression and defective oocyte specification. These findings establish NPC renewal as a critical step in oocyte identity establishment and maternal provisioning.

DOI: https://doi.org/10.64898/2026.02.13.705775
Nat Struct Mol Biol. 2026 Feb 25.

Transposable element-gene chimera cartography, origination and role in enhancing transcriptome plasticity.

Youngseo Cheon, Erik Glen Alvstad, Denis Torre, Daniel Tu Quach, Jennifer Nguyen, Kwangbeom Hyun, Mingqi Zhou, Tianxiong Yu, Liang Liu, Yoseop Yoon, Fairlie Reese, Lauren Faraone, Yingcong Li, Frederick J Arnold, Yesai S Fstkchyan, Uttiya Basu, Evgeny Kvon, Enza Maria Valente, Jessica Sook Yuin Ho, Minji Byun, Ernesto Guccione, Yongsheng Shi, Zhiping Weng, Marcus Seldin, Ivan Marazzi.

Transposable elements (TEs) in the human genome are the heritage of ancient parasitic infections. While most of human DNA comprises TEs and TE-derived elements, their repetitive nature poses technical challenges; thus, little is known about their positional identity and regulatory roles. Here, by integrating long-read and multidimensional transcriptional analyses, we investigate when, where and how TEs become part of a gene. We characterize how TE-derived isoforms change across mouse-human variation and how they are linked to gene regulatory networks controlling cell states during differentiation, organogenesis and health (aging and pathological states). Mechanistically, we identify an RNA degradation-dependent and splicing-dependent quality control mechanism that operates independently of conventional mechanisms of TE suppression, such as DNA methylation and heterochromatinization, and prevents TE-chimera expression and TE-induced cell differentiation. Overall, our findings unveil mechanisms by which viral-derived elements enhance transcriptome plasticity.

DOI: https://doi.org/10.1038/s41594-026-01757-z
bioRxiv. 2026 Feb 16. pii: 2026.02.15.706013. [Epub ahead of print]

Cell enlargement drives aging-associated proteome remodeling and shortens replicative lifespan.

Michael C Lanz, Manuel Hotz, Rachel Kroll-Ling, Eileen Wang, Jabob Kim, Joshua E Elias, Daniel E Gottschling, Jan M Skotheim.

The molecular and cellular basis of aging and its associated functional decline remains poorly understood. Even free-living microorganisms age and, in yeast, replicative aging shares key hallmarks with human cellular senescence, including progressive cell enlargement. Recent work has shown that chemical and genetic manipulations that increase cell size promote the onset of senescence in both yeast and human cells, suggesting that cell enlargement can drive some of the physiological changes associated with aging. Here, we quantitatively determined how cell enlargement contributes to age-associated physiology in yeast by combining automated aging technologies with quantitative proteomics. We find that the majority of aging-associated proteome remodeling can be recapitulated by genetically enlarging young proliferating cells. These enlarged cells exhibit accelerated proteome aging and shortened replicative lifespans, while smaller cells are longer-lived. While cell enlargement is the predominant factor driving proteome remodeling during aging, we also identified a minority of aging-specific molecular markers whose expression influences lifespan. Together, our results demonstrate that cell enlargement is a major driver of aging-associated proteome remodeling and influences lifespan independently of established aging factors such as extrachromosomal rDNA circles.

DOI: https://doi.org/10.64898/2026.02.15.706013
Nat Commun. 2026 Feb 26.

Single-cell transcriptomics reveals hair growth retardation mediated by aberrant connective tissue sheath contraction in male androgenetic alopecia.

Guo Li, Li Yang, Shixin Duan, Mengting Chen, Yujin Zhang, Fangfen Liu, Yunying Wang, Jiayun Li, San Xu, Zheng Wu, Mei Wang, Ben Wang, Zhixiang Zhao, Wei Shi, Mingxing Lei, Hongfu Xie, Yan Tang, Zhili Deng, Ji Li.

Androgenetic alopecia (AGA) manifests as progressive hair follicle (HF) miniaturization; however, its drivers remain poorly elucidated. Combining spatial and single-cell transcriptomics, we generate a concise single-cell atlas of anagen HFs in male AGA, revealing early changes in cell subpopulations, altered HF stem cell fate determination, and disrupted cell-cell communications. Through ex vivo HF organ culture and humanized mouse models, we demonstrate that hypercontractility of connective tissue sheath (CTS) activates the mechanosensitive channel PIEZO1 in anagen HFs. This mechanotransduction induces ectopic apoptosis of HF progenitor cells and suppresses matrix/ORS cell proliferation, depleting progenitor pools and impairing HF growth, thereby driving progressive miniaturization. Critically, pharmacological inhibition of CTS contraction via ML-7, a selective myosin light chain kinase (MLCK) inhibitor, improves HF growth in both male AGA patient-derived ex vivo models and humanized mice. Our study delineates the cellular dynamics underlying male AGA pathogenesis and identifies mechanopathologically activated CTS as a key driver of HF miniaturization, positioning the peri-follicular CTS as a promising therapeutic target for AGA intervention.

DOI: https://doi.org/10.1038/s41467-026-70153-4
Mol Cell. 2026 Feb 24. pii: S1097-2765(26)00094-8. [Epub ahead of print]

Nucleosome spacing regulates linker methylation by DNMT3A2/3B3.

Xiaoyan Xie, Minmin Liu, Gabriella N L Chua, X Edward Zhou, Michelle L Dykstra, Shixin Liu, Peter A Jones, Evan J Worden.

  De novo CpG methylation (mCpG) is deposited by DNMT3A and DNMT3B, which target DNA linkers between nucleosomes. Cells contain millions of unique linkers, but the rules dictating which linkers get targeted by DNMT3 enzymes are not understood. We show that nucleosome spacing controls linker DNA methylation and H3K36me2 recognition by human DNMT3A2/3B3, linking de novo methylation to chromatin architecture. We present structures of DNMT3A2/3B3 bound to dinucleosomes, revealing that short linkers promote dinucleosome bridging, blocking access to linker DNA and suppressing methylation, whereas long linkers allow DNMT3A2/3B3 to engage each nucleosome separately and methylate linker DNA. Finally, we show that DNMT3A2/3B3 positions proline-tryptophan-tryptophan-proline (PWWP) domains to scan for H3K36me2. However, H3K36me2 recognition is blocked when DNMT3A2/3B3 bridges dinucleosomes with short linkers, imposing an additional structural constraint on DNMT3A2/3B3 function. Together, these findings uncover the mechanisms that govern de novo methylation in chromatin and explain how DNMT3 enzymes target linkers in cells.

Keywords:  DNA methylation; DNA methyltransferase; cancer; chromatin; nucleosome

DOI:  https://doi.org/10.1016/j.molcel.2026.01.030
Nature. 2026 Feb 25.

Human hippocampal neurogenesis in adulthood, ageing and Alzheimer's disease.

Ahmed Disouky, Mark A Sanborn, K R Sabitha, Mostafa M Mostafa, Ivan Alejandro Ayala, David A Bennett, Yisha Lu, Yi Zhou, C Dirk Keene, Sandra Weintraub, Tamar Gefen, M-Marsel Mesulam, Changiz Geula, Mark Maienschein-Cline, Jalees Rehman, Orly Lazarov.

The existence of human hippocampal neurogenesis has long been disputed1-12 and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD)11,13. However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers)14,15, adults with preclinical intermediate pathology or adults with AD. Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

DOI: https://doi.org/10.1038/s41586-026-10169-4
J Cell Biol. 2026 Apr 06. pii: e202507134. [Epub ahead of print]225(4):

Two δ-catenins, plakophilin 4 and p120, promote formation of distinct types of adherens junctions.

Indrajyoti Indra, Regina B Troyanovsky, Farida V Korobova, Sergey M Troyanovsky.

Classical cadherins are instrumental for connecting cells into tissues by forming adherens junctions (AJs), a structurally diverse class of cell-cell adhesions tailored to specific membrane domains, cell types, and particular functions. The mechanisms that underlie the AJ diversification remain unknown. Here, we show that two δ-catenin family members, p120 and plakophilin 4 (pkp4), which bind the intracellular region of classical cadherins, promote distinct modes of cadherin clustering, thereby contributing to AJ specialization. The mode promoted by p120 is driven by interactions between cadherin-associated protein, α-catenin, and actin filaments. This "canonical" clustering mechanism generates apical and basal AJs that play a major role in overall cell-cell adhesion. The mode promoted by pkp4 is driven by an α-catenin-independent mechanism. It generates lateral AJs, which apparently function in processes other than cell-cell adhesion. Collectively, our findings show that δ-catenins regulate the balance between different AJ assembly pathways, thereby contributing to AJ diversification.

DOI: https://doi.org/10.1083/jcb.202507134
Nat Struct Mol Biol. 2026 Feb 27.

Stress adaptation of mitochondrial protein import by OMA1-mediated degradation of DNAJC15.

Lara Kroczek, Hendrik Nolte, Yvonne Lasarzewski, Ishita Agrawal, Thibaut Molinié, Daniel Curbelo Piñero, Kathrin Lemke, Elena Rugarli, Thomas Langer.

Mitochondria dynamically adapt to cellular stress to ensure cell survival. The stress-regulated mitochondrial peptidase OMA1 orchestrates these adaptive responses, which limit mitochondrial fusion and promote mitochondrial stress signaling and metabolic rewiring. Here, we show that cellular stress adaptation involves OMA1-mediated regulation of mitochondrial protein import and OXPHOS biogenesis. OMA1 cleaves the mitochondrial chaperone DNAJC15 and promotes its degradation by the m-AAA protease AFG3L2. Loss of DNAJC15 impairs mitochondrial protein import and restricts OXPHOS biogenesis under conditions of mitochondrial dysfunction. Non-imported mitochondrial preproteins accumulate at the endoplasmic reticulum, inducing an unfolded protein response. Our results demonstrate stress-dependent changes in mitochondrial protein import as part of the OMA1-mediated mitochondrial stress response and highlight the interdependence of proteostasis regulation between different organelles.

DOI: https://doi.org/10.1038/s41594-026-01756-0
bioRxiv. 2026 Feb 09. pii: 2026.02.08.704470. [Epub ahead of print]

Intercellular Communication via Mitotic Nanotubes is Influenced by Connexin-43 Trafficking and Actin Remodeling.

A Cooper, S Cetin-Ferra, K A Yonosh, A Hinton, A Marshall, J R Faeder, S A Murray.

Gap junction communication is reduced during mitosis as the junction protein connexin-43 (Cx43) is redistributed from gap junction plaques on the plasma membrane to cytoplasmic annular vesicles and actin-based mitotic nanotubes that transiently connect mitotic cells to neighboring cells. However, the dynamic details of Cx43 redistribution during cell entry into and exit from mitosis, and the roles of mitotic nanotubes and associated Cx43 in intercellular communication, remain poorly understood. Here, using confocal live-cell imaging, we show that as cells enter mitosis, plaque-derived Cx43 structures are transferred to mitotic nanotubes. Over time, these structures fragment and migrate along the length of the nanotubes, either being transferred to the cytoplasm of adjacent cells or being positioned at the nanotube ends where they could potentially enable communication. Functionally, mitotic nanotubes indeed facilitate gap junction-dependent intercellular communication, though at reduced rates compared interphase cells. Interestingly, knockdown of Cx43 resulted in impaired nanotube formation and intercellular communication while inhibition of Rho kinase (ROCK) with Y-27632 prevented mitotic cell rounding and nanotube elongation, and increased cell-cell communication during mitosis, suggesting that nanotube function is influenced by Cx43 expression and trafficking as well as actin remodeling via ROCK. Overall, these findings provide valuable insights into the mechanisms that regulate Cx43 and mitotic nanotube dynamics and reveal a novel role for mitotic nanotubes in facilitating cell-cell communication during cell division.

DOI: https://doi.org/10.64898/2026.02.08.704470
Cell Stem Cell. 2026 Feb 24. pii: S1934-5909(26)00038-X. [Epub ahead of print]

Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity.

Ming Zhu, Junsong Yuan, Qiuchen Meng, Jiawei Yu, Xiaoqing Xu, Mingyue Xu, Xiaoyu Ren, Yanyan Hu, Guoan Wei, Zeran Jia, Guohua Yuan, Lu Zang, Shaorui Liu, Yuanyuan Yang, Yuan Zheng, Jiacheng Wang, Tingting Cong, Wei Xie, Xun Lan, Le Cong, Tianhua Ma, Sheng Ding, Weixiang Guo, Xuegong Zhang, Yinqing Li.

  Although CRISPR-Cas9 holds therapeutic promise, broader application demands an understanding of complications in vast non-coding regions. We found that CRISPR-Cas9 can cause premature differentiation of neural stem cells in vivo and mouse embryonic stem cells in vitro, even when cleavage occurred at distant sites tens of kilobases away from the nearest regulatory elements. To investigate this, we employed an integrated assay for transposase-accessible chromatin (ATAC)/RNA sequencing (AR-seq) approach and identified editing-induced chromatin accessibility changes, with their scale varying by cell type. Cells with stemness are most affected, experiencing perturbations that extend over a hundred kilobases. Furthermore, even local DNA perturbations can disrupt CTCF- and condensate-associated chromatin architecture, causing distal transcriptional rewiring and, ultimately, loss of stemness identity. To minimize chromatin perturbations and preserve cell identity, we refined gene-editing strategies, including distance-aware sgRNA design, pharmacological attenuation of DNA resection, and alternative editing systems. This work paves the way for the safer and broader application of genome-editing technologies.

Keywords:  chromatin architecture; chromatin condensate; chromatin perturbation; genome editing; neural stem cell; premature differentiation; somatic stem cell

DOI:  https://doi.org/10.1016/j.stem.2026.01.015
Nat Commun. 2026 Feb 27. pii: 2051. [Epub ahead of print]17(1):

Activation of IRF3 in cardiomyocytes impairs mitochondrial oxidative function through PGC-1α inhibition and drives heart failure.

Manju Kumari, Ioannis Evangelakos, Anushka Deshpande, Kirstie A De Jong, Nesrin Schmiedel, Nicolàs Palacio-Escat, Adriano de Britto Chaves-Filho, Roberto Carlos Frias-Soler, Glynis Klinke, Hyun Cheol Roh, Luisa Lange, Michael Berlin, Marceline M Fuh, Jakob Johannes Buss, Tian Tian, Carolin Lerchenmüller, Marc Freichel, Almut Schulze, Viacheslav O Nikolaev, Thomas Eschenhagen, Evan D Rosen, Ludger Scheja, Ashraf Yusuf Rangrez, Joerg Heeren, Norbert Frey.

Heightened sterile inflammation and mitochondrial metabolic dysfunction drives the pathophysiology of heart failure in ischemic cardiomyopathy. Yet, the transcriptional regulators within cardiomyocytes driving crosstalk between inflammation and energy metabolism remain ill-defined. Here we identify elevated Ser396/Ser398 phosphorylation of the type I interferon (IFN) response regulating transcription factor IRF3 in the myocardium of patients and male mice with ischemic cardiomyopathy. Cardiomyocyte-specific IRF3 deficiency attenuates ischemia induced contractile dysfunction. Conversely, IRF3 activation in cardiomyocytes through a phosphomimetic IRF3 mutant represses Ppargc1α expression leading to dysfunctional mitochondrial oxidative phosphorylation, altered metabolic flux in the pentose phosphate pathway/TCA cycle, impaired NAD metabolism and an excessive type I IFN activation, collectively detrimental for cardiac function. Restoring cardiomyocyte-specific Ppargc1α expression in IRF3-overexpressor male mice attenuates contractile dysfunction by augmenting a metabolic shift towards fatty acid oxidation and decreasing inflammatory fibrotic responses. These findings identify IRF3 activation in cardiomyocytes as a transcriptional nexus between cardiac inflammation and metabolic fuel switch contributing to heart failure progression.

DOI: https://doi.org/10.1038/s41467-026-69792-4
Genes Dev. 2026 Feb 23.

α-Satellite RNA marks the perinucleolar compartment and represses ribosomal RNA expression in naive human embryonic stem cells.

Kirti Mittal, Lamisa Ataei, Miguel Ramalho-Santos.

  While most newly synthesized RNA is exported to the cytoplasm, a portion of noncoding RNA is retained in the nucleus and remains highly associated with chromatin. The strong binding of this RNA fraction to insoluble chromatin impairs its recovery in standard transcriptomic studies. Therefore, the landscape and potential functions of chromatin-associated RNAs are poorly understood. Recent studies indicate that chromatin-associated transcripts can have regulatory roles, particularly during mammalian development. Here we compare the dynamics of cytoplasmic versus chromatin-bound transcriptomes of naive and primed human embryonic stem cells (hESCs) as well as fibroblasts. We found a remarkable enrichment for RNA transcribed from α-satellite repeat (ALR) in the chromatin fraction of naive hESCs compared with primed hESCs. The colocalization and interaction of ALR RNA with polypyrimidine tract binding protein 1 (PTBP1) and CUG-binding protein (CUGBP) indicate that ALR RNA foci mark the perinucleolar compartment (PNC), a nuclear subcompartment previously thought to be exclusive to cancer cells. Knockdown of ALR RNA leads to dispersion of PTBP1/CUGBP foci, upregulation of ribosomal RNA, and global hypertranscription in naive hESCs. In contrast, loss of PTBP1 does not disturb ALR RNA localization, indicating that ALR is upstream in the hierarchy of organization of the PNC in hESCs. These results reveal a role for ALR RNA in nuclear compartmentalization and tuning rRNA synthesis in naive hESCs. Moreover, this study opens new avenues to dissect the function of ALR RNA and the PNC in cancer contexts.

Keywords:  PTBP1; chromatin-associated RNA; human embryonic stem cells; nucleolus; perinucleolar compartment; ribosomal RNA; α-satellite RNA

DOI:  https://doi.org/10.1101/gad.353162.125
Science. 2026 Feb 26. 391(6788): eaea0296

Reconstitution of sex determination and the testicular niche using mouse pluripotent stem cells.

Takashi Yoshino, Hiromichi Sasada, Takuya Sato, Tomonori Nakamura, Kenjiro Shirane, Hiroshi Ohta, Maki Kamoshita, Miki Inoue, Yuki Matsudaira, Chao Liu, Minatsu Matsufuji, Makoto Tachibana, Ken-Ichirou Morohashi, Masahito Ikawa, Mitinori Saitou, Takehiko Ogawa, Katsuhiko Hayashi.

Proper differentiation of gonadal somatic cells is crucial for sex determination and the production of sex hormones and gametes, and reconstituting this process in culture would both deepen our understanding of this process and enable the generation of gametes in vitro. Here, we report the reconstitution of testicular somatic cells using mouse pluripotent stem cells. The reconstitution recapitulated the sex-determination process, yielding cell types that formed seminiferous tubules and adjacent interstitial tissues. The reconstituted testicular tissue incorporated pluripotent stem cell-derived primordial germ cells and supported their differentiation into spermatogonial stem cells. These spermatogonial stem cells differentiated into functional spermatozoa upon transplantation into testis. This study contributes to a deeper understanding of the sex-determination process and to the creation of an alternative source for the male germ line in culture.

DOI: https://doi.org/10.1126/science.aea0296
Nat Immunol. 2026 Feb 27.

Reciprocal regulation of fibroblast-macrophage equilibrium governs skin integrity.

Apple Cortez Vollmers, Sunny Z Wu, Anthony Altieri, Erika E McCartney, Hannah Bender, Christopher D Davidson, Wyne P Lee, Juan Zhang, Crystal Hu, Surinder Jeet, Ben Hall, Ricardo A Irizarry-Caro, Alberto Guarnieri, Endi K Santosa, Jessica Preston, Salil Uttarwar, Jason A Vander Heiden, Yein Chung, Willie Ortiz, Michael Long, Raymond Asuncion, Yeqing Angela Yang, Jean X Jiang, Zora Modrusan, Subba Chintalacharuvu, Christine Moussion, Akshay T Krishnamurty, Wenxian Fu, Sören Müller, Matthew B Buechler, Shannon J Turley.

Fibroblast-macrophage crosstalk is well-established in vitro, and fibroblast-derived colony-stimulating factor 1 (CSF1) supports macrophages in select tissues. However, whether macrophages regulate fibroblasts in vivo remains unknown. Leveraging genetic mouse models, single-cell multi-omics, flow cytometry and imaging, we show that fibroblast depletion or loss of fibroblast-derived growth factors impacts skin macrophage populations in the dermis and hypodermis. Conditional deletion of Csf1 in Dpt+ fibroblasts progressively decreases CD64+ and CD11c+ macrophages, impairing skin wound healing. Reduced macrophage abundance disrupts fibroblast cell cycle regulation, metabolism and immune signaling, and increases fibroblast abundance, affirming a reciprocal relationship. In human systemic sclerosis (scleroderma), elevated fibroblast-derived CSF1 and increased macrophage abundance correlate with disease severity, implicating the CSF1-CSF1R axis in pathology. These findings provide in vivo evidence of macrophage regulation of fibroblasts, revealing a bidirectional interplay that advances understanding of tissue homeostasis and immune regulation in skin.

DOI: https://doi.org/10.1038/s41590-026-02434-5
Aging (Albany NY). 2026 Feb 10. 18(1): 30-44

Aging-associated mitochondrial circular RNAs.

Hyejin Mun, Do-Won Ham, Nam Chul Kim, Bo-In Kwon, Young-Kook Kim, Je-Hyun Yoon.

  During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs. Although global profiles of the human transcriptome and epitranscriptome during the aging process are available, the existence and function of mitochondrial circular RNAs originating from the mitochondrial genome are poorly studied. Here, we report profiles of circular RNAs annotated to mitochondrial chromosome, chrM, in young and old cohorts. The most abundant circular RNA junctions are found in MT-RNR2, whose level is depleted in old cohorts and senescent fibroblast. The mitochondria-localized RNA-binding protein GRSF1 binds various mitochondrial transcripts, including linear and circular MT-RNR2, with a distinct RNA motif. Linear and circular MT-RNR2 bind a subset of TCA cycle enzymes, suggesting their possible function in regulating glucose metabolism in mitochondria to preserve proliferating status in young cohorts. In human fibroblasts, depletion of GRSF1 reduced levels of circMT-RNR2 and fumarate/succinate, concomitantly accelerating cellular senescence and mitochondrial dysfunction. Taken together, our findings demonstrate the existence and possible function of circular MT-RNR2 during human aging and senescence, implicating its role in promoting the TCA cycle.

Keywords:  GRSF1; MT-RNR2; TCA cycle; aging; circular RNA

DOI:  https://doi.org/10.18632/aging.206354
Nat Phys. 2026 Feb;22(2): 275-286

Collective transitions from orbiting to matrix invasion in three-dimensional multicellular spheroids.

Jiwon Kim, Hyuntae Jeong, Carles Falcó, Alex M Hruska, W Duncan Martinson, Alejandro Marzoratti, Mauricio Araiza, Haiqian Yang, Vera C Fonseca, Stephen A Adam, Christian Franck, José A Carrillo, Ming Guo, Ian Y Wong.

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bidirectional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. In turn, orbiting along sharper curvature results in locally stronger contractile tractions, which gradually align collagen fibers in the radial direction. Thus, the initially elongated morphology primes the matrix towards subsequent invasion of two to four strands that are roughly aligned with the major axis. We then show that orbiting can be arrested and invasion can be reversed using osmotic pressure. We also investigate coordinated orbiting in mosaic spheroids, showing a small fraction of cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Altogether, this work elucidates how symmetry-breaking in tissue morphogenesis is governed by the interplay of collective migration and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.

DOI: https://doi.org/10.1038/s41567-025-03150-x
bioRxiv. 2026 Feb 10. pii: 2026.02.09.704880. [Epub ahead of print]

Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis.

Alexandra Bermudez, Zoe Latham, Johnny Diaz, Weihong Yan, Jerry Chen, Dapeng Bi, Andrew Goldstein, Jimmy K Hu, Neil Y C Lin.

Epithelial tissues undergo dynamic transitions between fluid-like collective motion and mechanically jammed states during development, injury repair, and disease progression. However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multi-omics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition. Functional inhibition of mitochondrial pyruvate import is sufficient to sustain collective cell motility, impeding jamming transition in crowded cells. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility. These findings identify mitochondrial pyruvate utilization as a key regulator that links metabolic remodeling to the endocytic control of epithelial fluidity.

DOI: https://doi.org/10.64898/2026.02.09.704880
Cell Stem Cell. 2026 Feb 23. pii: S1934-5909(26)00031-7. [Epub ahead of print]

Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens.

Feiyu Yang, Narciso Pavon, Tatsuya Matsubara, Rebecca Sebastian, Beatriz Martinez-Martin, ChangHui Pak, Yubing Sun, Deok-Ho Kim.

  Positional patterning during human brain development is orchestrated through highly coordinated interplays of locally produced inductive signals. Although animal models have elucidated general signaling pathways during early neurodevelopment, individual morphogens' effects underlying the proper human brain regionalization remain unclear. Current technologies are limited in generating stable, well-confined gradients in neural organoids for robust regionalization. Here, we report a Matrigel-free passive diffusion-based morphogen gradient generator (PdMG) that reliably established a steep exogenous spatial morphogen gradient in human neural organoids. We further established dorsal-ventral forebrain, rostral-caudal fore-midbrain-like, and rostral-caudal fore-hindbrain-like patterning by applying Sonic hedgehog/Wingless/int1 (WNT) inhibitor, WNT, and retinoic acid gradients, respectively. Spatial transcriptomics analysis revealed robust regionalization in early-stage patterned organoids, as well as active neurogenesis and γ-aminobutyric acid (GABAergic) interneuron migrations in late-stage patterned organoids. Together, this study provides a framework for modeling the spatial-temporal morphogen dynamics that regulate key cell fate specifications and axis formations using patterned neural organoid models.

Keywords:  dorsal-ventral; morphogen gradient; neural organoid; patterning; rostral-caudal

DOI:  https://doi.org/10.1016/j.stem.2026.01.008
PLoS Pathog. 2026 Feb;22(2): e1013991

Baculoviruses exploit the mitotic kinase CDK1 to disrupt the nuclear lamina.

Mei Mo, Silan Yu, Yushan Yang, Jiongjiong Liu, Kai Yang, Meijin Yuan.

The nuclear lamina is disassembled during mitosis, and certain DNA viruses exploit this process to facilitate replication. While we previously showed that baculoviruses disrupt the exogenously integrated lamina, their impact on the endogenous structure, the underlying mechanism, and the functional consequences for viral replication remained unknown. Here, we demonstrate that baculovirus infection triggers endogenous nuclear lamina disassembly, and that phosphorylation of lamin B at the N-terminal "mitotic site" serine 47 (S47) is the key event driving this process. Using in vitro phosphorylation assays, phospho-specific reagents, and site-directed mutagenesis, we further show that baculoviruses exploit the mitotic kinase cyclin-dependent kinase 1 (CDK1) to directly phosphorylate S47, thereby disrupting the lamina. Critically, this baculovirus-induced lamina disruption is not an epiphenomenon; transmission electron microscopy and viral titer assays demonstrate it is essential for the efficient nuclear egress of nucleocapsids and the production of infectious budded virions. Our study thus defines a distinct mechanism of viral subversion, wherein a virus directly repurposes the core mitotic machinery to breach the nuclear lamina barrier, a finding that significantly advances our understanding of host‒pathogen conflict.

DOI: https://doi.org/10.1371/journal.ppat.1013991
Cell. 2026 Feb 25. pii: S0092-8674(25)01507-7. [Epub ahead of print]

Whole-organ and whole-body 3D atlases enable cellome-wide profiling.

Shota Y Yoshida, Katsuhiko Matsumoto, Satoshi Takagi, Fukuaki L Kinoshita, Katsunari Yamashita, Daichi Shigeta, Yoshichika Yoshioka, Tetsuo Ushiku, Eiichi Morii, Etsuo A Susaki, Hiroki R Ueda.

  Recent advancements in tissue clearing and light-sheet fluorescence microscopy have enabled whole-organ/body-scale analysis at single-cell resolution. However, comprehensive bioinformatics resources like digitized whole-cellome maps, analogous to whole-genome sequencing, remain limited. Here, we present the CUBIC Organ/Body Atlas, a set of three-dimensional single-cell-resolution references for eleven adult mouse organs and a neonatal whole-mouse body. To generate this atlas, we optimized tissue clearing protocols and developed exMOVIE, an imaging system achieving sufficient working distance and axial resolution for organ-/body-wide three-dimensional imaging and subsequent cell nuclei detection. The atlas facilitates comparative analysis among multiple samples at single-cell resolution, allowing for applications in organ development studies, disease state analysis, and whole-body immune cell profiling with three-dimensional immunostaining. Thus, the CUBIC Organ/Body Atlas contributes to establishing a common cellomics workflow, advancing our systems-level understanding of organisms in physiological, developmental, and pathological processes.

Keywords:  3D imaging; CUBIC; atlas; cellome-wide profiling; cellomics; immune system; light-sheet fluorescence microscopy; tissue clearing; whole body; whole organ

DOI:  https://doi.org/10.1016/j.cell.2025.12.057
Nat Commun. 2026 Feb 25.

ERCC6L2 ensures repair fidelity for staggered-end DNA double-strand breaks.

Eric J Aird, Almudena Serrano-Benitez, Sebastian M Siegner, Elda Cannavo, Rimma Belotserkovskaya, Nadia Gueorguieva, John Fielden, Grégoire Cullot, Sandra Ammann, Aldo S Bader, Vipul Gupta, Geoffroy Andrieux, Rebecca Raab, Mónica Del Rey González, Toni Cathomen, Petr Cejka, Jacob E Corn, Stephen P Jackson.

DNA double-strand breaks (DSBs) both pose threats to genome integrity and are commonly used for genome editing applications. Structural features of DSB ends play key roles in determining DNA repair pathway usage and outcomes during genome editing, but the cellular factors involved in these processes are only partially known. Through genome-wide CRISPRi screening, we identify ERCC6L2 as critical for repairing Cas12a-induced staggered DSBs but irrelevant for Cas9-induced blunt DSBs. We show that ERCC6L2 acts as a protection factor for staggered DSBs with either 5' or 3' polarity, preventing large deletions and translocations stemming from DNA damage induced by Cas12a, TALENs, or dual Cas9 nicks. Furthermore, ERCC6L2 loss hyper-sensitizes cells to multiple staggered DSBs induced by promiscuous Cas12a activity or etoposide-induced TOP2 trapping. By combining genetics and biochemical reconstitution, we find that ERCC6L2 counteracts MRE11-RAD50-NBS1 (MRN)-mediated resection by binding and melting staggered DNA ends, thereby promoting accurate end joining. Our data reveal a protective role of ERCC6L2 in staggered-end DSB repair, which suggests the molecular underpinnings of pathology in patients with ERCC6L2 mutations and cautions against using overhang-inducing genome editing tools for their treatment.

DOI: https://doi.org/10.1038/s41467-026-69843-w
Angew Chem Int Ed Engl. 2026 Feb 27. e24603

1,3-Dicarbonyl Rhodamines for Live-Cell Single-Molecule Super-Resolution Imaging.

Qiang Peng, Yangfan Wang, Bei Zheng, Zijing Yu, Shasha Zhuang, Yongdeng Zhang, Dan Yang.

  1,3-Dicarbonyl compounds, with their diverse and intriguing chemical properties, have found broad applications in fields such as organic synthesis, pharmaceuticals, luminescent materials, and personal care products. Here, we integrated the 1,3-dicarbonyl scaffold with rhodamine-based fluorophores to construct a series of 1,3-dicarbonyl-rhodamine derivatives. By exploiting the intrinsic thermodynamic and photochemical properties of 1,3-dicarbonyl compounds, these rhodamine derivatives enable sparse localization, tunable emitter density, and a self-triggered photooxidation cascade under single- or dual-laser irradiation. These features render them suitable for single-molecule localization microscopy (SMLM). Using click chemistry, HaloTag labeling, and phospholipid-targeting groups, we achieved super-resolution imaging and dynamic tracking of actin, the endoplasmic reticulum, mitochondria, and the plasma membrane in live cells. Notably, under low laser intensity, a rich repertoire of filopodia dynamics was resolved in live cells over an extended 20 min time course (encompassing 120,000 total frames). The imaging achieved a spatial localization accuracy of 22 nm and a temporal resolution of 20 s, enabling high-fidelity tracking of dynamic cellular protrusions.

Keywords:  1,3‐Dicarbonyl compounds; rhodamine; super‐resolution imaging

DOI:  https://doi.org/10.1002/anie.202524603
Nat Commun. 2026 Feb 25.

Targeting de novo pyrimidine synthesis confers vulnerability to copper-mediated ATR inactivation in PARP inhibitor-resistant ovarian cancer.

Yabing Nan, Kunyu Wang, Menghan Hu, Qingyu Luo, Xiaowei Wu, Xiao Yu, Xuantong Zhou, Li Chen, Bin Li, Zhumei Cui, Zhihua Liu.

Although poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) as monotherapy or in combination with other DNA-damaging agents exhibit promising clinical efficacy, the therapeutic responses are usually transient, with subsequent development of acquired resistance posing a significant challenge. Here, through a small-molecule compound screening, we identify elesclomol, a potent copper ionophore, which sensitizes BRCA-proficient ovarian cancer cells to PARPi by inhibiting activation of the ATR-CHK1 pathway. Mechanistically, we demonstrate that copper directly binds to ATRIP, a critical cofactor of ATR activation, disrupting the ATR-ATRIP interaction, further impairing ATR-mediated DNA damage repair signaling and potentiating PARPi sensitivity. Importantly, we reveal a secondary metabolic vulnerability in PARPi-resistant ovarian cancer associated with de novo pyrimidine synthesis, suggesting that targeting this pathway as an effective strategy to eradicate drug-adaptive residual tumors and resistant patient-derived xenograft models following ATR and PARP co-inhibition. These findings propose de novo pyrimidine synthesis as an adaptive metabolic vulnerability that can be therapeutically targeted to overcome PARPi resistance in BRCA-proficient ovarian cancer.

DOI: https://doi.org/10.1038/s41467-026-70001-5
Sci Adv. 2026 Feb 27. 12(9): eadz0269

Generation of functionally competent testicular somatic cells from pluripotent stem cells.

Takuya Sato, Takashi Yoshino, Mai Ohtsuka, Takahiro Suzuki, Takafumi Matsumura, Yuki Matsudaira, Yu Ishikawa-Yamauchi, Shiori Maeda, Haruka Yabukami, Yoshiakira Kanai, Miki Inoue, Yuichi Shima, Makoto Tachibana, Shogo Matoba, Kimiko Inoue, Narumi Ogonuki, Atsuo Ogura, Katsuhiko Hayashi, Takehiko Ogawa.

Cellular interactions between germ cells and gonadal somatic cells are essential for the progression of gametogenesis. Here, we report a culture method for generating fetal testicular somatic cell-like cells (fTeSLCs) from embryonic stem cells. These fTeSLCs exhibit a transcriptomic profile closely resembling that of their in vivo counterparts, including distinct cell populations corresponding to Sertoli cells and interstitial cells. For functional assessment, interstitial cell-like cells (ICLCs) and Sertoli-like cells (SerLCs) were isolated from fTeSLCs. ICLCs differentiated into Leydig cells when cocultured with testes lacking endogenous Leydig cells, thereby restoring androgenic support. SerLCs reconstituted the seminiferous epithelium following selective ablation of endogenous Sertoli cells. Both cell types supported spermatogenesis and generated spermatids reaching the elongating stage. Notably, round spermatids derived from these reconstructed systems produced viable offspring by round spermatid injection. These findings demonstrate that fTeSLCs can generate functional testicular somatic cells, providing a valuable platform for studying testis development and spermatogenesis.

DOI: https://doi.org/10.1126/sciadv.adz0269
Nat Commun. 2026 Feb 24.

iCLAP: an innovative method for integrable co-detection of low-abundance antigens with high-plex immunostaining.

Fan Wu, Shuyuan Zheng, Yani Chen, Peijia Ye, Moo Joong Kim, Seojin Lee, Geroge Kuo, Shriya Pillan, Ruihan Yuan, Kyu Sang Han, Bofei Yu, Qingfeng Zhu, Sarah M Shin, Courtney D Cannon, Gabriele Pierre, Kanako Iwasaki, Cristina Aguayo-Mazzucato, Nicolas Musi, George A Kuchel, Birgit Schilling, Laura D Wood, Won Jin Ho, Robert A Anders, Denis Wirtz, Pei-Hsun Wu.

Multiplexed protein imaging enables spatial analysis of complex tissues, but detecting proteins expressed at low levels remains challenging, particularly in widely available formalin-fixed, paraffin-embedded (FFPE) specimens. Many biologically important regulators-including senescence markers, transcription factors, and secreted proteins-are therefore difficult to study in situ using existing high-plex methods. Here we show that integrable Co-detection of Low-Abundant Proteins (iCLAP) enables sensitive and highly multiplexed protein detection within the same FFPE tissue section. iCLAP combines iterative signal amplification with efficient fluorophore inactivation, enabling repeated staining of the same tissue section and seamless integration with established multiplex imaging platforms to achieve profiling of more than 40 markers. Application of iCLAP to human pancreatic tissues revealed spatially distinct senescence-associated protein patterns across tissue compartments. Together, iCLAP expands the analytical capabilities of FFPE tissues, enabling high-sensitivity, high-dimensional spatial proteomic studies of complex biological processes.

DOI: https://doi.org/10.1038/s41467-026-69752-y
Mol Cell. 2026 Feb 24. pii: S1097-2765(26)00071-7. [Epub ahead of print]

The human antibacterial factor APOL3 couples lysosomal damage to mitochondrial DNA efflux and type I IFN induction.

Dominic A Ritacco, Hamna Shahnawaz, Antonia Oduguwa, Jacob Hawk, Brianna Vizcaino, Donna L Farber, Ryan G Gaudet.

  Lysosomal damage is an endogenous danger signal, but its significance for innate immunity and the specific signaling pathways it engages remain unclear. Here, we uncover an immune-inducible pathway that connects lysosomal damage to mitochondrial DNA (mtDNA) efflux and type I IFN production. We find that transient lysosomal damage elicits sub-lethal mitochondrial outer membrane permeabilization (MOMP) via BAK/BAX macropores; however, the inner mitochondrial membrane (IMM) maintains a barrier against wholesale mtDNA release. Priming with type II IFN (IFN-γ) induced the antibacterial factor APOL3, which, upon sensing lysosomal damage, targets mitochondria undergoing MOMP to selectively permeabilize the IMM, enhance mtDNA release, and potentiate downstream cGAS signaling. Biochemical and cellular reconstitution revealed that, analogous to its bactericidal detergent-like mechanism, APOL3 permeabilized the IMM by solubilizing cardiolipin. Our findings illustrate how cells enlist an antibacterial protein to expedite the breakdown of endosymbiosis and facilitate a heightened response to injury and infection.

Keywords:  DNA; damage; innate immunity; interferon; intracellular bacteria; lysosome; mitochondrion; viruses

DOI:  https://doi.org/10.1016/j.molcel.2026.01.029
bioRxiv. 2026 Feb 11. pii: 2026.02.10.705189. [Epub ahead of print]

Nup42 safeguards heat-induced mRNAs from nuclear condensation to support chaperone synthesis.

Eduardo Tassoni-Tsuchida, Angel Madero, Magda Zaoralová, Sebastian Alfonso, Brian Alford, Onn Brandman.

Cells exposed to acute stress selectively express stress-adaptive genes while repressing growth-related genes. Upon heat shock, most pre-existing mRNAs localize to translationally repressed biomolecular condensates. How heat-induced mRNAs evade condensation and remain translationally competent remains unclear. Here, we show that ribosomal protein-coding transcripts preferentially accumulate in condensates during heat shock, whereas heat-induced chaperone mRNAs are selectively excluded and preferentially translated. Using a whole-genome CRISPRi screening platform, Fractionation of Reporter-Seq (FRep-Seq), we identify the nucleoporin Nup42 as the strongest suppressor of heat-induced mRNA condensation. Loss of Nup42 triggers temperature- and transcription-dependent nuclear condensation of chaperone mRNAs, which are exported but remain translationally incompetent, leading to impaired chaperone production and thermosensitivity. Co-transcriptional mRNP packaging is a critical determinant of condensation in the absence of Nup42. Together, our findings reveal a nuclear, translation-independent layer of mRNP solubility control that enables heat shock gene expression.

DOI: https://doi.org/10.64898/2026.02.10.705189
Nucleic Acids Res. 2026 Feb 24. pii: gkag173. [Epub ahead of print]54(5):

Nascent transcriptome of embryonic genome activation reveals a regulatory axis linking transcriptional priming to early lineage specification in mouse embryos.

Yue Hu, Yuxiang Wang, Maosheng Ye, Yuanlin He, Zhangyi Ouyang, Chao Ren, Tianyin Miao, Siqi Wang, Ou Zhong, Li Liu, Wenjie Shu, Ran Huo.

Embryonic genome activation (EGA) marks a critical developmental transition, yet its regulatory architecture remains incompletely defined. Here, we employed optimized low-input SLAM-seq (thiol(SH)-linked alkylation for the metabolic sequencing) to map the temporal hierarchy of nascent transcription during mouse EGA. We uncovered patterns of transcriptional priming characterized by pre-activated genes (PAGs) with permissive chromatin states, followed by pronounced accumulation of PAGs-encoded proteins in blastocysts, suggesting that EGA memory propagates from early transcriptional activation to later lineage commitment. Furthermore, Integrative analysis nominated two-cell nascent transcription factors (TFs) as candidate regulators of the first lineage specification. Functional investigations demonstrated KLF17 as a key TF linking EGA to the first lineage specification via regulation of PAGs transcription. KLF17 deficiency led to the failure of transcriptional activation in approximately half of PAGs at the two-cell stage. Our work provides a detailed framework for decoding mammalian EGA and offers insights into how embryonic transcriptional priming is coordinated with early cell fate specification.

DOI: https://doi.org/10.1093/nar/gkag173
Cell Metab. 2026 Feb 23. pii: S1550-4131(26)00016-1. [Epub ahead of print]

Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis.

Eva Novoa, Tamara Parracho, Julica Inderhees, Amaia Rodriguez, Cristina Riobello, Jose Iglesias-Moure, Anabel Fernández-Iglesias, Sara Martinez-Martinez, Ana Senra, Samuel Seoane, Marcos Fondevila, Cristina Iglesias, Alba Cabaleiro, Natalia da Silva Lima, Valentina Dorta, Borja López-Picallo, Lucia Ramos-Lage, Ashwin Woodhoo, Miguel Fidalgo, Maria L Martínez-Chantar, Francisco Javier Cubero, Miguel López, Carlos Dieguez, Diana Guallar, Vincent Prevot, Robert Schwabe, Gema Frühbeck, Javier Crespo, Marta Varela-Rey, Maria J Gonzalez-Rellan, Jordi Gracia-Sancho, Paula Iruzubieta, Markus Schwaninger, Ruben Nogueiras.

  Phosphoenolpyruvate carboxykinase 1 (PCK1) is a key integrator of hepatic energy metabolism, but its role in hepatic stellate cells (HSCs), the main fibrogenic cells in the liver, remains unknown. We found that PCK1 is reduced in HSCs from fibrotic animals and people with fibrosis, correlating negatively with fibrosis severity. Silencing PCK1 activates human HSCs and increases fibrotic markers, whereas ectopic PCK1 expression blunts transforming growth factor β1 (TGF-β1)-induced activation. Activated HSCs show elevated glycolysis and tricarboxylic acid (TCA) cycle activity, but PCK1 overexpression reduces acetyl-coenzyme A (CoA), limiting TCA cycle intermediates and ameliorating HSC activation. In mice, HSC-specific PCK1 loss accelerates diet-induced liver fibrosis. Notably, mice lacking PCK1 in HSCs also develop spontaneous fibrosis on a normal diet. These findings show that disrupted cataplerosis from PCK1 loss enhances glycolysis and activates HSCs, promoting liver fibrosis.

Keywords:  PCK1; glycolysis; hepatic stellate cells; liver fibrosis; metabolism

DOI:  https://doi.org/10.1016/j.cmet.2026.01.016
Nat Commun. 2026 Feb 25.

The nuclease EXO1 promotes genomic instability by degrading nascent DNA in BRCA-proficient cells.

Alexandra Nusawardhana, Claudia M Nicolae, George-Lucian Moldovan.

DNA repair genes are generally considered tumor suppressors, as their inactivation is observed in tumors and is associated with carcinogenesis. Mutations in BRCA1 and BRCA2 genes are observed in breast, ovarian, and other cancers. This results in defective homologous recombination DNA repair, as well as in degradation of nascent DNA during replication stress, catalyzed by exonucleases including EXO1 and MRE11. However, most tumors are BRCA pathway-proficient. Here, we show that EXO1 is overexpressed in a significant proportion of tumors. EXO1 overexpression causes the degradation of nascent DNA at both single stranded DNA (ssDNA) gaps and reversed replication forks. Importantly, this degradation occurs efficiently in BRCA-proficient cells, through cooperation with MRE11. This results in increased double strand break formation and hypersensitivity to genotoxic agents. We thus identify increased EXO1 activity as a mechanism of genomic instability similar to BRCA pathway inactivation, but occurring more frequently in tumors compared to BRCA inactivation.

DOI: https://doi.org/10.1038/s41467-026-69981-1
Res Sq. 2026 Feb 09. pii: rs.3.rs-8704827. [Epub ahead of print]

Hematopoietic stem cell aging promotes TET2 clonal hematopoiesis.

James DeGregori, Marco De Dominici, Lamis Naddaf, Angelica Varesi, Andrew Goodspeed, Bridget Hoag, Vadym Zaberezhnyy, Johannes Menzel, Yang Liu, Stephanie Xie, Sheng Li.

Aging is strongly associated with the incidence of clonal hematopoiesis (CH) and myeloid malignancies. However, the role of aging in the clonal selection for CH mutations is not well understood. In a mouse model of CH, we observe that transplanted Tet2 KO hematopoietic stem cells (HSC) from old donor mice expand at a faster rate than young irrespective of the age of the recipient mice; that this acceleration is observed by middle age; and that it is primarily due to the aging-associated reduction in fitness of aged competitor non-mutant HSC. Mechanistically, in both mice and humans, we found that aged HSC exhibit enhanced activation of a RUNX1 transcriptional program and increased expression of ribosomal protein genes inducing a p53-mediated stress response, and that these changes are abrogated by Tet2/TET2 inactivation. Thus, aging creates the conditions that foster clonal expansion of Tet2, Runx1 and Trp53 mutant HSC promoting CH.

DOI: https://doi.org/10.21203/rs.3.rs-8704827/v1
Nucleic Acids Res. 2026 Feb 24. pii: gkag146. [Epub ahead of print]54(5):

A de novo H3.2K9me2 deposition pathway establishes heterochromatin for suppressing transposon mobilization during fly somatic development.

Yi Ni Luo, Yazi Deng, Yu Liang, Wei Wu, Wei Wu, Lu Wang.

Histone variants along with their associated chaperones have been considered as one of the major complexes to provide versatility in organizing chromatin structure. Post-translational modifications (PTMs) of H3 variants serve as very important factors in promoting heterochromatin assembly, protecting telomere stability, and suppressing transposon activity. However, the precise mechanism by which specific PTMs on H3 variants suppress transposons remains elusive. Here, by monitoring retrotransposon mobilization during Drosophila hindgut development, we identified the DNA synthesis-coupled (DSC) H3.2K9me2 deposition pathway as a pivotal mechanism for transposon suppression. Depleting the factors in the DSC H3.2 complex, but not in the DNA synthesis-independent (DSI) H3.3 chaperone pathway, unleashed massive retrotransposon activation. DSC chaperones specifically establish dimethylation at the H3.2K9 site in heterochromatic regions by directly interacting with and recruiting the histone methyltransferase, G9a. Intriguingly, the cross-talk between DSC H3.2K9me2 and DSI H3.3K9me3 in heterochromatin is dynamically regulated and properly balanced. Although DSI H3.3K9me3 could efficiently be incorporated into transposon loci when the DSC H3.2K9me2 deposition pathway was disrupted, H3.3K9me3 alone was insufficient to establish functional heterochromatin required for transposon silencing during development. Altogether, our discoveries provide a framework to understand how cells employ specific histone variant modifications to construct and maintain heterochromatin, thereby ensuring transposon repression and safeguarding genome integrity.

DOI: https://doi.org/10.1093/nar/gkag146
Dev Cell. 2026 Feb 23. pii: S1534-5807(26)00040-7. [Epub ahead of print]

A lineage-specific selective autophagy receptor module mediates P-body turnover.

Alibek Abdrakhmanov, Elizabeth Ethier, Aleksandra S Anisimova, Nenad Grujic, Ranjith K Papareddy, Marion Clavel, G Elif Karagöz, Erinc Hallacli, Yasin Dagdas.

  Processing bodies (P-bodies) are conserved ribonucleoprotein granules central to RNA metabolism across eukaryotes. Although the mechanisms underlying their assembly are well understood, the pathways governing their selective turnover remain unclear. Here, we identify the conserved decapping proteins Enhancer of mRNA decapping 4 (EDC4) and decapping protein 1 (DCP1) as a selective autophagy receptor pair responsible for P-body turnover in the model plant Marchantia polymorpha. MpEDC4 engages ATG8 via a canonical ATG8-interacting motif, while MpDCP1 contains a previously unrecognized reverse ATG8-interacting motif within its intrinsically disordered region. Mutations disrupting these motifs impair the autophagic degradation of P-bodies, demonstrating a cooperative receptor mechanism. Notably, this autophagic function is lineage-specific, as orthologs in Arabidopsis and humans lack ATG8-binding capacity. Strikingly, the heterologous expression of MpEDC4 in human cells promotes the degradation of α-synuclein, a protein linked to Parkinson's disease etiology. Our findings uncover an evolutionary innovation that links RNA metabolism to selective autophagy and open avenues for the cross-kingdom engineering of targeted protein degradation pathways.

Keywords:  ATG8; Marchantia; P-body; RNP-granules; autophagic flux; receptor engineering; selective autophagy; selective autophagy receptor; targeted protein degradation; α-synuclein degradation

DOI:  https://doi.org/10.1016/j.devcel.2026.01.017
Nat Struct Mol Biol. 2026 Feb 26.

Integrator subunit INTS12 links ribotoxic stress to transcription-coupled nucleotide excision repair.

Zhuo Li, Ran Li, Min Yang, Yanchao Huang, Jiaye Yang, Qian Zhu, Yangqing Shao, Weiqi Zhao, Huanyi Fu, Yu-Xin Xiao, Chengyu Li, Huipeng Jiao, Dong Fang, Bing Yang, Yi Lu, Jun Xu, Lei Li, Jun Huang, Fei Xavier Chen, Long Zhang, Jinchuan Hu, Huasong Lu.

Cells use transcription-coupled nucleotide excision repair (TC-NER) to efficiently resolve transcription-blocking DNA lesions caused by genotoxic stress such as ultraviolet (UV) irradiation. However, UV also induces RNA damage, triggering a cytoplasmic ribotoxic stress response (RSR). Whether and how RSR affects nuclear TC-NER has remained unclear. Here we identify INTS12, a flexible, poorly characterized subunit of the Integrator complex, as a key mediator linking RSR to TC-NER. Specifically, RSR-activated ZAK signaling induces phosphorylation of INTS12, enhancing its interaction with CSB and promoting recruitment of the Integrator complex to lesion-stalled RNA polymerase II (Pol II). This facilitates Pol II clearance and enables efficient DNA repair through TC-NER. Disruption of this pathway compromises TC-NER and transcription recovery, thereby increasing cellular sensitivity to UV-induced damage. Notably, the requirement for INTS12-mediated Pol II removal is context dependent, as it is not advantageous during the transcription-coupled response to formaldehyde-induced DNA-protein crosslinks, which rely on a distinct proteasome-dependent degradation pathway. Together, these findings uncover a regulatory axis connecting RNA damage signaling to DNA repair and highlight a context-dependent role of INTS12 in maintaining genome integrity.

DOI: https://doi.org/10.1038/s41594-026-01766-y