Nuclear pores safeguard the integrity of the nuclear envelope

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 5, 2024

Abstract Nuclear pore complexes (NPCs) constitute giant channels within the nuclear envelope that mediate nucleocytoplasmic exchange. NPC diameter is thought to be regulated by tension, but how such changes are physiologically linked cell differentiation, where mechanical properties of nuclei remodeled and mechanosensing occurs, remains unstudied. Here we used cryo-electron tomography show NPCs dilate during differentiation mouse embryonic stem cells into neural progenitors. In Nup133-deficient cells, which known display impaired however fail dilate. By analyzing architectures individual with template matching, revealed structurally heterogeneous frequently disintegrate, resulting in formation large openings. We propose elasticity scaffold mechanically safeguards envelope. Our studies provide a molecular explanation for genetic perturbation scaffolding components macromolecular causes tissue-specific phenotypes.

Language: Английский

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Ku70 Binding to YAP Alters PARP1 Ubiquitination to Regulate Genome Stability and Tumorigenesis

Cancer Research, Journal Year: 2024, Volume and Issue: 84(17), P. 2836 - 2855

Published: June 11, 2024

Abstract Yes-associated protein (YAP) is a central player in cancer development, with functions extending beyond its recognized role cell growth regulation. Recent work has identified link between YAP/transcriptional coactivator PDZ-binding motif (TAZ) and the DNA damage response. Here, we investigated mechanistic underpinnings of cross-talk repair YAP activity. Ku70, key component nonhomologous end joining pathway to damage, engaged dynamic competition TEAD4 for binding YAP, limiting transcriptional activity YAP. Depletion Ku70 enhanced interaction boosted capacity. Consequently, loss tumorigenesis colon hepatocellular carcinoma (HCC) vivo. impeded elevated genome instability by inducing PARP1 degradation through SMURF2-mediated ubiquitin-proteasome pathway. Analysis samples from patients HCC substantiated expression, activity, levels, instability. In conclusion, this research provides insight into interactions regulators repair, highlighting Ku70-YAP-PARP1 axis preserving stability. Significance: Increased yes-associated stimulated induces upregulating SMURF2 inhibit driving tumorigenesis.

Language: Английский

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Deciphering mechanical cues in the microenvironment: from non-malignant settings to tumor progression

Biomarker Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 23, 2025

The tumor microenvironment functions as a dynamic and intricate ecosystem, comprising diverse array of cellular non-cellular components that precisely orchestrate pivotal behaviors, including invasion, metastasis, drug resistance. While unraveling the interplay between behaviors represents tremendous challenge, recent research illuminates crucial biological phenomenon known mechanotransduction. Within microenvironment, mechanical cues like tensile stress, shear stiffness play role by activating mechanosensitive effectors such PIEZO proteins, integrins, Yes-associated protein. This activation initiates cascades intrinsic signaling pathways, effectively linking physical properties tissues to their physiological pathophysiological processes morphogenesis, regeneration, immunity. mechanistic insight offers novel perspective on how within impact behaviors. intricacies are yet be fully elucidated, it exhibits distinct attributes from non-malignant tissues, elevated solid stresses, interstitial hypertension, augmented matrix stiffness, enhanced viscoelasticity. These traits exert notable influences progression treatment responses, enriching our comprehension multifaceted nature microenvironment. Through this innovative review, we aim provide new lens decipher contexts, broadening knowledge these factors promote or inhibit thus offering valuable insights identify potential targets for anti-tumor strategies.

Language: Английский

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Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint

Nature Cell Biology, Journal Year: 2025, Volume and Issue: 27(1), P. 73 - 86

Published: Jan. 1, 2025

Errors during cell division lead to aneuploidy, which is associated with genomic instability and transformation. In response cells activate the tumour suppressor p53 elicit a surveillance mechanism that halts proliferation promotes senescence. The molecular sensors trigger this checkpoint are unclear. Here, using tunable system of chromosome mis-segregation, we show mitotic errors nuclear deformation, softening, lamin heterochromatin alterations, leading rapid p53/p21 activation upon exit in changes mechanics. We identify mTORC2 ATR as deformation upstream activation. While triggering arrest, mis-segregation-induced alterations envelope mechanics provide fitness advantage for aneuploid by promoting resilience enhancing pro-invasive capabilities. Collectively, work identifies mechanical triggered altered chromatin organization probably plays critical role cellular transformation cancer progression. Hervé, Scelfo et al. mis-segregation induces mTORC2- ATR-mediated through mechanosensitive at content increased membrane tension.

Language: Английский

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Substrate stiffness dictates unique doxorubicin-induced senescence-associated secretory phenotypes and transcriptomic signatures in human pulmonary fibroblasts

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Language: Английский

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Feeling the force from within – new tools and insights into nuclear mechanotransduction

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(5)

Published: March 1, 2025

The ability of cells to sense and respond mechanical signals is essential for many biological processes that form the basis cell identity, tissue development maintenance. This process, known as mechanotransduction, involves crucial feedback between force biochemical signals, including epigenomic modifications establish transcriptional programs. These programs, in turn, reinforce properties its withstand perturbation. nucleus has long been hypothesized play a key role mechanotransduction due direct exposure forces transmitted through cytoskeleton, receiving cytoplasmic central function gene regulation. However, parsing out specific contributions from those surface cytoplasm remains substantial challenge. In this Review, we examine latest evidence on how regulates both via nuclear envelope (NE) epigenetic machinery elements within interior. We also explore establishing memory, characterized by mechanical, transcriptomic state persists after stimuli cease. Finally, discuss current challenges field present technological advances are poised overcome them.

Language: Английский

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Mitochondria derived from Stem cells modulated the biological behavior of monocyte-macrophages and inhibited inflammatory bone resorption

BMC Musculoskeletal Disorders, Journal Year: 2025, Volume and Issue: 26(1)

Published: March 22, 2025

The transfer of mitochondria from stem cells effectively attenuates the viability inflammatory cells. However, there is a paucity research supporting inhibitory effect on bone resorption through mitochondrial transfer. Mouse models were established to investigate impact cell-derived mitochondria. Stem cells, and exosomes injected into animal for experimental research. Healthy mice with included as control groups. calvaria evaluated by immunofluorescence, gross morphology, micro-computed tomography (micro-CT), immunohistochemical staining. Monocyte-macrophages incubated group. activated monocyte-macrophages cultured separately served biological behavior enzyme-linked immunosorbent assay (ELISA), Multiskan FC, histochemical successfully transferred monocyte-macrophages. In vivo, local injection mitochondria, mitigated cell infiltration, suppressed osteoclast maturation, demonstrated higher relative volume in mouse compared negative vitro, co-incubation secretion cytokines, proliferation, fusion, osteoclastogenesis modulation behaviors may occur thereby mitigating resorption.

Language: Английский

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At the nucleus of cancer: how the nuclear envelope controls tumor progression

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 24, 2025

Abstract Historically considered downstream effects of tumorigenesis—arising from changes in DNA content or chromatin organization—nuclear alterations have long been seen as mere prognostic markers within a genome‐centric model cancer. However, recent findings placed the nuclear envelope (NE) at forefront tumor progression, highlighting its active role mediating cellular responses to mechanical forces. Despite significant progress, precise interplay between NE components and cancer progression remains under debate. In this review, we provide comprehensive up‐to‐date overview how composition affect mechanics facilitate malignant transformation, grounded latest molecular functional studies. We also review research that uses advanced technologies, including artificial intelligence, predict malignancy risk treatment outcomes by analyzing morphology. Finally, discuss progress understanding has paved way for mechanotherapy—a promising approach exploits differences cancerous healthy cells. Shifting perspective on diagnostic potential therapeutic targets, calls further investigation into evolving cancer, innovative strategies transform conventional therapies.

Language: Английский

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Actin from within – how nuclear myosins and actin regulate nuclear architecture and mechanics

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(3)

Published: Feb. 1, 2025

Over the past two decades, significant progress has been made in understanding mechanotransduction to nucleus. Nevertheless, most research focused on outside-in signalling orchestrated by external mechanical stimuli. Emerging evidence highlights importance of intrinsic nuclear mechanisms mechanoresponse. The discovery actin and associated motor proteins, such as myosins, nucleus, along with advances chromatin organisation research, raised new questions about contribution intranuclear architecture mechanics. Nuclear myosins are present various compartments particularly at sites DNA processing modification. These proteins can function hubs scaffolds, cross-linking distant regions thereby impacting local global membrane shape. Importantly, force-sensitive cooperates mechanosensors, suggesting a multi-level crosstalk between implications for cell plasticity prevention pathological conditions. Here, we review recent impactful findings that highlight roles organisation. Additionally, discuss potential links these emphasize using methodologies unravel nuclear-derived regulatory distinct from cytoskeleton.

Language: Английский

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ATR-hippo drives force signaling to nuclear F-actin and links mechanotransduction to neurological disorders

Science Advances, Journal Year: 2025, Volume and Issue: 11(7)

Published: Feb. 14, 2025

The mechanical environment is sensed through cell-matrix contacts with the cytoskeleton, but how signals transit nuclear envelope to affect cell fate decisions remains unknown. Nuclear actin coordinates chromatin motility during differentiation and genome maintenance, yet it unclear responds force. DNA-damage kinase ataxia telangiectasia Rad3-related protein (ATR) translocates protect nucleus or compression. Here, we show that ATR drives assembly via recruitment of Filamin-A inner membrane binding hippo pathway scaffold substrate, RASSF1A. Moreover, demonstrate germline RASSF1 mutation disables mechanotransduction resulting in cerebral cortex thinning associates common psychological traits. Thus, defective mechanical-regulated pathways may contribute complex neurological disorders.

Language: Английский

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