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At least 19 recordsLinked to original sources
PubMed2026

Small GTPase RAN-driven PNET2 oligomerization and phase separation at the nuclear lamina promote nuclear envelope integrity in plants.

The nuclear envelope is a fundamental organizer of eukaryotic cells, yet how plants regulate its architecture and integrity remains poorly understood. In this study, we identified the plant inner nuclear membrane protein PLANT NUCLEAR ENVELOPE TRANSMEMBRANE 2 (PNET2) as a scaffold that maintains nuclear envelope integrity and genome stability. Loss of PNET2 function compromises nuclear membrane structure and sensitizes cells to DNA damage, whereas overexpression drives aberrant nuclear membrane expansion. Biochemically, PNET2 cooperates with the nuclear lamin protein KAKU4 and CROWDED NUCLEI 1 within the nuclear lamina to promote nuclear membrane remodeling, a process driven by biomolecular condensate formation via their intrinsically disordered regions. We further uncovered a direct interaction between PNET2 and the small GTPase RAN. Structural modeling and biochemical analyses revealed that its active GTP-bound form stimulates PNET2 oligomerization, potentially promoting its phase separation to drive membrane expansion. Genetic analyses showed that PNET2 and RAN function in a shared pathway essential for nuclear membrane integrity. Together, our findings define a regulatory module that orchestrates GTPase signaling to sustain nuclear membrane homeostasis in plants, positioning PNET2 as a nexus linking membrane dynamics, nuclear lamina organization, and genome protection.

PNET2↗
PubMed2025

Unraveling Plant Nuclear Envelope Composition Using Proximity Labeling Proteomics.

The nuclear envelope (NE) defines the eukaryotic cell and functions in a myriad of fundamental cellular processes including but not limited to signal transduction, lipid metabolism, chromatin organization, and nucleocytoplasmic transportation. Although the general structure of the NE is well-conserved across eukaryotic kingdoms, its composition and functions vary substantially between species and remain largely unknown in plants. In this chapter, we describe a proximity-labeling-based proteomic approach to profile novel NE components in the model organism Arabidopsis. This method is generally suitable for the identification of protein components in subcellular compartments or protein complexes that are poorly accessible to traditional mass spectrometry approaches and can be easily applied to other plant species. In addition to giving a step-by-step detailed description of the proximity labeling proteomics procedure in plant samples, we also provide guidelines on the appropriate use of controls and statistical analysis to achieve a highly specific selection of probed candidates.

Proteomics↗
PubMed2026

Integrative chemical genetics platform identifies condensate modulators linked to neurological disorders.

Dysregulation of biomolecular condensates is implicated across multiple neurological disorders. However, approaches to systematically identify their modulators remain limited. Here, we expand the utility of MLF2 as a versatile condensate biomarker and develop CondenScreen, an integrated high-content screening and bioinformatics pipeline enabling identification of condensate modulators across chemical and genetic space. Screening 1760 bioactive compounds in a cellular DYT1 dystonia model, we validate the platform for condensate-targeted drug discovery, identifying drugs that prevent the accumulation of the MLF2 reporter into nuclear envelope condensates. In parallel, a genome-wide CRISPR/Cas9 screen correlates nuclear condensate abundance with genes implicated in microcephaly and over eight additional neurodevelopmental disorders. Machine learning and confocal imaging resolve distinct condensate phenotypes, with RNF26 deletion provoking nuclear envelope condensates that phenocopy hallmarks of torsin deficiency. Our study provides a scalable platform for identifying modulators of condensates and establishes a correlative connection between nuclear condensate accumulation and genes implicated in neurodevelopmental disorders.

Humans↗
PubMed2024

SUN2 mediates calcium-triggered nuclear actin polymerization to cluster active RNA polymerase II.

The nucleoskeleton is essential for nuclear architecture as well as genome integrity and gene expression. In addition to lamins, titin or spectrins, dynamic actin filament polymerization has emerged as a potential intranuclear structural element but its functions are less well explored. Here we found that calcium elevations trigger rapid nuclear actin assembly requiring the nuclear membrane protein SUN2 independently of its function as a component of the LINC complex. Instead, SUN2 colocalized and associated with the formin and actin nucleator INF2 in the nuclear envelope in a calcium-regulated manner. Moreover, SUN2 is required for active RNA polymerase II (RNA Pol II) clustering in response to calcium elevations. Thus, our data uncover a SUN2-formin module linking the nuclear envelope to intranuclear actin assembly to promote signal-dependent spatial reorganization of active RNA Pol II.

RNA Polymerase II↗
PubMed2025

Zea mays Meiotic Spindle Ultrastructure Reveals Kinetochore-Microtubule Interface and Embedded Membrane Components.

UNLABELLED: Introduction: Spindles are microtubules-based machines whose primary function is to accurately segregate chromosomes in both mitotic and meiotic cell division. The structure of spindles is critical for their function; errors in morphology or attachment to chromosomes lead to aneuploidy, potentially resulting in disease, infertility, and lethality. Electron microscopy studies have yielded fine-detail spindle ultrastructures in many plant and animal species, but no studies have investigated the spindle of Zea mays, a critical crop, and cytogenetic model system. METHODS: Here we use electron tomography (ET), reconstruction, and modeling to obtain three-dimensional, nanometer-resolution of the Z. mays meiotic spindle. Structures such as microtubules, kinetochores, vesicles, membrane channels, and nuclear envelope were modeled through a partial spindle reconstruction, and confirmed using immunostaining and live fluorescence microscopy. RESULTS: ET revealed that maize spindles contain 8-18 kinetochore microtubules (kMTs) per kinetochore, which are approximately 776 nm in diameter and 316 nm in depth. Small ∼37 nm vesicles were identified, as well as larger (∼5 µm long, 800 nm wide) membrane structures with channels that allow spindle microtubules to pass through. These membrane channels stain positively for the ER-marker protein disulfide isomerase. Imaging of prophase meiotic cells revealed a cross-hatch microtubule arrangement in the perinuclear ring on the external surface of the nuclear envelope, which also contained type II nuclear grooves with transnuclear microtubules passing from the nucleus to the cytoplasm. CONCLUSIONS: Z. mays meiotic spindles are similar to animal counterparts with a comparable number of kMTs and pre-spindle transnuclear microtubules but also plant-specific features such as Golgi-derived vesicles to assist cell plate formation, internal ER membrane channels, and a perinuclear microtubule ring that aids spindle assembly. Maize kinetochores have an electron-diffuse ball in cup morphology that is comparable in size to Drosophila kinetochores and larger than mammalian kinetochores. .

Zea mays↗
PubMed2025

An Optimized Adaptation of DamID for NGS Applications.

Recent studies have implicated higher-order genome organization in the regulation of genes and cellular state. Lamina-Associated Domains (LADs) are regions of heterochromatin associated with the nuclear envelope and the nuclear lamina, a protein network involved in both nuclear organization and genome structure. LADs are developmentally regulated, and their dysregulation is associated with several diseases and pathological states, including cancer and premature aging. In addition to LADs, other nuclear protein compartments appear to scaffold or support unique chromatin environments to affect gene expression. These revelations carry profound implications for our comprehension of developmental processes and the pathogenesis of various diseases, especially given the numerous disorders already directly associated with, for example, mutations in lamin and INM proteins. This spatial compartmentalization of chromatin subtypes to unique protein compartments has led to the adoption of proximity-labeling methods, such as DamID (DNA Adenine Methyltransferase Identification), to identify these unique chromatin compartments.

Humans↗
PubMed2026

Participation of the purinergic P2X7 receptor in molecular complexes in the nucleus of human chondrocytes.

In addition to the purinergic receptor P2X7R's known activity as a sensor of damage-associated molecular patterns (DAMPs), evidences support its role in maintaining tissue homeostasis. Its presence in cellular compartments other than its usual transmembrane localization suggests its involvement in specific signaling pathways. This study aimed to analyze P2X7R in the nucleus of human chondrocytes and search for potential interacting partners. Through co-immunoprecipitation and proximity ligation assay we discovered that, independent of extracellular ATP levels, P2X7R is abundantly present in both the nuclear membrane and in the nucleoplasm, where it is found in close proximity to lamin A/C (a component of the nuclear lamina), emerin (a protein involved in the assembly and disassembly of the nuclear envelope), and SUN2 (an inner nuclear membrane protein that facilitates the transmission of mechanical forces). Furthermore, chromatin immunoprecipitation revealed the participation of P2X7R in molecular complexes located in the promoter of specific genes including Sox9, TRPS1, FOXO3a, integrin β2 and connective tissue growth factor. Overall, this evidence reveals for the first time novel partners of P2X7R that place it in an intricate network that influences nuclear structure, mechanosensitivity, chromatin organization, and gene expression. Specifically, on the one hand, a close association between P2X7R and nuclear proteins participating in the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex (lamin A/C, emerin, and SUN2) places it among the factors involved in mechanosignaling and the maintenance of nuclear integrity; on the other, its recruitment to specific gene promoters suggests that it may act as a transcription regulator.

Humans↗
PubMed2025

Effects of Lamina-Chromatin Attachment on Super Long-Range Chromatin Interactions.

The interactions between chromatin and lamin proteins localized on the nuclear envelope play a crucial role in the three-dimensional (3D) organization of the genome. This study investigates the influence of lamin associated domains (LADs) on genome organization at the chromosome level using 3D polymer models of mouse embryonic fibroblasts (MEFs) and embryonic stem cells (mESCs). By integrating genome-wide LAD maps from DamID assays, we simulated chromatin conformations with and without LAD attachment to the nuclear envelope. Our results show that incorporating LAD-lamin interactions yields a radial chromatin distribution consistent with experimental observations. Moreover, LAD-lamin interactions induce significant super long-range chromatin contacts across distant genomic regions. These findings suggest two distinct mechanisms driving induction of chromatin interactions by LAD-lamin attachment.

3D single cell conformations↗
PubMed2026

The role of SYNE1/2 variants as a potential predisposition factor for the onset of endometriosis.

Endometriosis (EM) is a chronic, inflammatory gynaecological disorder defined by the presence of endometrial-like tissue outside the uterine cavity, most frequently affecting the ovaries, peritoneum, and uterosacral ligaments. Despite its prevalence and the significant impact on life quality, EM is often underdiagnosed, with an average delay of about nine years, particularly affecting adolescents and young women. The complex aetiology involves genetic, environmental, and immune factors, with whole-exome sequencing (WES) emerging as a potential tool for identifying relevant genetic variants. Research indicates that innate immune dysfunction, mechanotransduction, and epithelial-to-mesenchymal transition promote endometrial cell migration and lesion formation, processes regulated by nuclear envelope integrity and cytoskeletal dynamics. The LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, specifically Nesprin-1 and Nesprin-2, encoded by SYNE1 and SYNE2, is crucial for these processes. Genome-wide studies have linked SYNE genes to EM risk, showing downregulation in affected patients, and rare variants in these genes have been identified, though their functional implications are still unclear. To this purpose, WES was performed on 204 EM patients to identify rare (MAF <0.1%), damaging variants in SYNE1/2. Primary endometriotic cells (EMCs) were isolated from ovarian lesions of variant carriers (n=4) and wild-type (WT) non-carrier controls (n=4). Functional characterization included somatic WES, RT-qPCR, Western blot, confocal immunofluorescence, and Transwell migration assays. WES identified 11 rare, likely damaging SYNE1/2 variants in 12 patients. Immunofluorescence revealed a distinct protein mislocalization, WT EMCs displayed physiological Nesprin-2 confinement at the nuclear envelope, whereas variant carriers exhibited a diffuse cytoplasmic distribution polarized along actin stress fibres. We demonstrated that SYNE1/2 mutated EMCs had a markedly higher migratory capacity compared to WT controls. Here, in vitro experiments demonstrated, for the first time, the involvement of Nesprin-2 in endometrial cell migration, supporting a mechanistic link between nuclear-cytoskeletal disruption and the invasive phenotype of endometriotic cells (EMCs). These findings provide new insights into EM pathogenesis and highlight SYNE2 as a promising molecular marker for improved diagnosis and disease management.

Humans↗
PubMed2025

The Dynamics of the ESCRT Machinery in Open Mitosis from Physiology to Pathology.

The Endosomal Sorting Complex Required for Transport (ESCRT) is a highly conserved machinery best known for its role in endosomal trafficking and membrane remodeling. Increasing evidence shows that ESCRT components are also key regulators during open mitosis, where precise membrane dynamics are essential for nuclear envelope reformation and spindle disassembly. In this review, we explore how the ESCRT machinery coordinates mitotic processes under physiological conditions and how their dysregulation contributes to genomic instability, altered cell division, and disease. We highlight recent findings on the spatiotemporal control of ESCRT recruitment at mitotic membranes, the interplay with chromatin and nuclear envelope-associated factors, and the consequences of defective ESCRT function in pathological contexts such as cancer and neurodegeneration. By connecting molecular mechanisms with cellular outcomes, we provide an integrated view of how the ESCRT machinery acts as critical guardian of mitotic fidelity and offer some routes for the identification of potential therapeutic targets in human disease.

Humans↗
PubMed2025

Nuclear rupture in confined cell migration triggers nuclear actin polymerization to limit chromatin leakage.

Upon cell migration in confined space, such as during cancer metastasis, mechanical forces from the extracellular matrix act onto the nucleus leading to nuclear envelope (NE) rupture, chromatin leakage and genomic instability. Here we found that during confined migration, NE rupture triggers dynamic nuclear F-actin formation dependent on the formins DIAPH1 and DIAPH3. We show that DIAPH3 dynamically and transiently relocates to the nucleus upon NE rupture. Interfering with DIAPH1/3 or with nuclear actin polymerization resulted in nuclear instability during confined migration. Notably, nuclear formin activity or actin assembly limit NE rupture-induced chromatin leakage. Similarly, silencing of Ataxia Telangiectasia and Rad3-related protein (ATR) reduced NE rupture-triggered nuclear F-actin assembly and increased chromatin leakage. Consistent with this, ATR promotes the phosphorylation of DIAPH3 at S1072 adjacent to its autoregulatory domain to promote nuclear actin polymerization. Using atomic force microscopy, we found that nuclear actin assembly or nuclear DIAPH3 activity promotes nuclear stiffness in an ATR-dependent manner. Thus, our study identifies an ATR-formin module that regulates nuclear mechanical properties through induction of intranuclear actin scaffolding.

Formins↗
PubMed2025

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol. 26, 2651-2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus 9, 258-275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun. 2, 503-517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

Lamin Type A↗
PubMed2025

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNA's role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging.

Biological Sciences↗
PubMed2025

Temporal gating of nuclear import: How Merkel cell polyomavirus exploits the cell cycle for nuclear entry.

Merkel cell polyomavirus (MCPyV) is a small, DNA tumor virus that is causally linked to an aggressive form of human skin cancer called Merkel cell carcinoma. MCPyV is the only polyomavirus definitively shown to cause cancer in humans, yet little is known about how it establishes infection in target cells. In this study, we report an unconventional mechanism by which MCPyV enters the host cell nucleus, where viral genome replication occurs. We demonstrate that, unlike other known polyomaviruses, MCPyV does not require the nuclear pore complex during entry. Instead, it takes advantage of cell cycle-dependent nuclear envelope breakdown to deliver its genetic material into the nucleus. We further show that the VP1 major capsid protein is sufficient to facilitate this process. Overall, our findings reveal a novel mechanism of polyomavirus nuclear entry and provide insight into the diverse mechanisms that these viruses use to cause infection.

Merkel cell polyomavirus↗
PubMed2026

CK2&#x3b1; restriction of STING accumulation underlies systemic aging.

Chronic activation of the cGAS-STING pathway drives inflammaging and cellular senescence. Although nuclear envelope (NE) barrier failure leading to cytoplasmic chromatin leakage is a key trigger, the molecular mechanisms governing STING activity at the NE during aging remain poorly understood. Here, we identify lamin A/C (LMNA) as a critical NE scaffold that orchestrates STING regulation by recruiting both STING and Casein Kinase 2 (CK2&#x3b1;). We demonstrate that LMNA facilitates the phosphorylation of STING at Ser366 by CK2&#x3b1;, which promotes STING turnover and restricts its accumulation, thereby attenuating pathway activation and mitigating senescence in myeloid cells as well as systemic aging. Strikingly, pharmacologic STING inhibition in vivo robustly rescues progeroid phenotypes-including loss of bone density and multi-tissue senescence-and extends lifespan in progeroid mouse models. Moreover, H-151 treatment also ameliorates the premature aging phenotypes induced by myeloid-specific CK2&#x3b1; ablation. In contrast, constitutive STING ablation yields limited survival benefits, revealing that controlled attenuation of STING signaling, rather than complete elimination, drives therapeutic efficacy. Our findings establish the LMNA-CK2-STING axis as a key biochemical mechanism that suppresses innate immune activation at the NE, offering a promising strategy for ameliorating aging and progeroid pathologies.

Animals↗
PubMed2026

Live dynamics of induced cell-cell fusion between mitotic and interphasic cells.

The cell cycle is tightly regulated by checkpoint mechanisms that ensure faithful duplication and segregation of the genome. Here, we induced cell-cell fusion between mitotic and interphase cells to study how nuclei from different cell cycle stages behave in a shared cytoplasm. We found that mitosis is a dominant cell cycle state: the mitotic cytoplasm can drive interphase nuclei into mitosis, whereas, in high ratios of interphase versus mitotic nuclei, fusion forced mitotic nuclei to exit mitosis. Both outcomes represent checkpoint override events with impactful consequences. Interphase nuclei forced into mitosis form aberrant mitotic spindles, show partially condensed DNA and ultimately undergo mitotic catastrophe. Conversely, forced mitotic exit resulted in reformation of nuclear envelope membranes around condensed chromosomes, forming nuclei with a defective nuclear import machinery. Altogether, cell-cell fusion revealed the consequences of checkpoint override, forcing nuclei through untimely cell cycle transitions, and highlight how cell-cell fusion experiments can be a powerful system to study how competing cytoplasmic states are integrated in a shared cytoplasm, such as in muscle, placenta formation and in cancer.

Cell cycle↗
PubMed2026

Alternative bipartite arrangements of VP1 BR1-3 drive efficient nuclear import of AAV2 capsids.

Adeno-associated viruses (AAVs) are among the most extensively studied viral gene-therapy vectors, yet the mechanisms governing their nuclear entry remain incompletely understood. Efficient transduction requires that the AAV capsid, or its structural subunit VP1, traverse the nuclear envelope to deliver the therapeutic genome. The N-terminal region of VP1 contains three clustered basic regions (BR1-3) proposed to function as nuclear localization signals (NLSs). Here, we combine cellular, biophysical, structural, and computational modelling approaches to define the nuclear import mechanism of AAV2 VP1 at molecular resolution. We show that VP1 engages the classical importin-&#x3b1;/&#x3b2;1 (IMP&#x3b1;/&#x3b2;1) pathway and binds multiple IMP&#x3b1; paralogs with distinct affinities. Crystallographic and mutational analyses reveal that two intact BRs are required to simultaneously occupy the major and minor binding pockets of IMP&#x3b1; in a bipartite configuration. Structural data indicate that mouse IMP&#x3b1;2 (mIMP&#x3b1;2) preferentially accommodates BR1 and BR3 at these sites, however, functional studies demonstrate that mutation of individual BRs does not abolish IMP binding or nuclear accumulation. This robustness arises from the ability of BR2 to flexibly engage both binding pockets, enabling the formation of alternative bipartite arrangements (BR1-BR2, BR2-BR3, or BR1-BR3). Together, these findings reveal an unexpected versatility in how AAV2 VP1 exploits the IMP&#x3b1; binding sites, providing a structural basis for efficient capsid nuclear import. The flexibility of BR1-3 expands the current paradigm of viral NLS organization and suggests new strategies to fine-tune nuclear targeting AAV-based gene-therapy vectors.

Adeno-associated virus↗