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Cell Sep 2021Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced...
Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.
Topics: Animals; Breast Neoplasms; Cell Line; Cellular Senescence; Collagen; DNA Damage; Disease Progression; Exodeoxyribonucleases; Female; Humans; Mice; Neoplasm Invasiveness; Nuclear Envelope; Phosphoproteins; Proteolysis; Xenograft Model Antitumor Assays
PubMed: 34551315
DOI: 10.1016/j.cell.2021.08.035 -
Science (New York, N.Y.) Apr 2016During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we...
During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.
Topics: Cell Line, Tumor; Cell Movement; Chromatin; Cytoplasm; DNA Damage; Endosomal Sorting Complexes Required for Transport; Humans; Lamins; Neoplasms; Nuclear Envelope; Stress, Mechanical; Tumor Microenvironment
PubMed: 27013428
DOI: 10.1126/science.aad7297 -
Nature Cell Biology Sep 2023The nuclear envelope (NE) is a spherical double membrane with elastic properties. How NE shape and elasticity are regulated by lipid chemistry is unknown. Here we...
The nuclear envelope (NE) is a spherical double membrane with elastic properties. How NE shape and elasticity are regulated by lipid chemistry is unknown. Here we discover lipid acyl chain unsaturation as essential for NE and nuclear pore complex (NPC) architecture and function. Increased lipid saturation rigidifies the NE and the endoplasmic reticulum into planar, polygonal membranes, which are fracture prone. These membranes exhibit a micron-scale segregation of lipids into ordered and disordered phases, excluding NPCs from the ordered phase. Balanced lipid saturation is required for NPC integrity, pore membrane curvature and nucleocytoplasmic transport. Oxygen deprivation amplifies the impact of saturated lipids, causing NE rigidification and rupture. Conversely, lipid droplets buffer saturated lipids to preserve NE architecture. Our study uncovers a fundamental link between lipid acyl chain structure and the integrity of the cell nucleus with implications for nuclear membrane malfunction in ischaemic tissues.
Topics: Nuclear Envelope; Nuclear Pore; Cell Nucleus; Elasticity; Lipids
PubMed: 37591950
DOI: 10.1038/s41556-023-01207-8 -
Nucleus (Austin, Tex.) Jul 2017Nuclear lamins are intermediate filament proteins that represent important structural components of metazoan nuclear envelopes (NEs). By combining proteomics and...
Nuclear lamins are intermediate filament proteins that represent important structural components of metazoan nuclear envelopes (NEs). By combining proteomics and superresolution microscopy, we recently reported that both A- and B-type nuclear lamins form spatially distinct filament networks at the nuclear periphery of mouse fibroblasts. In particular, A-type lamins exhibit differential association with nuclear pore complexes (NPCs). Our studies reveal that the nuclear lamina network in mammalian somatic cells is less ordered and more complex than that of amphibian oocytes, the only other system in which the lamina has been visualized at high resolution. In addition, the NPC component Tpr likely links NPCs to the A-type lamin network, an association that appears to be regulated by C-terminal modification of various A-type lamin isoforms. Many questions remain, however, concerning the structure and assembly of lamin filaments, as well as with their mode of association with other nuclear components such as peripheral chromatin.
Topics: Animals; Fibroblasts; Lamin Type A; Lamin Type B; Metabolic Networks and Pathways; Mice; Nuclear Envelope; Protein Isoforms
PubMed: 28901826
DOI: 10.1080/19491034.2017.1296616 -
Journal of Cell Science Jul 2019Cellular nuclei are bound by two uniformly separated lipid membranes that are fused with each other at numerous donut-shaped pores. These membranes are structurally... (Review)
Review
Cellular nuclei are bound by two uniformly separated lipid membranes that are fused with each other at numerous donut-shaped pores. These membranes are structurally supported by an array of distinct proteins with distinct mechanical functions. As a result, the nuclear envelope possesses unique mechanical properties, which enables it to resist cytoskeletal forces. Here, we review studies that are beginning to provide quantitative insights into nuclear membrane mechanics. We discuss how the mechanical properties of the fused nuclear membranes mediate their response to mechanical forces exerted on the nucleus and how structural reinforcement by different nuclear proteins protects the nuclear membranes against rupture. We also highlight some open questions in nuclear envelope mechanics, and discuss their relevance in the context of health and disease.
Topics: Animals; Humans; Mechanical Phenomena; Membrane Lipids; Models, Biological; Nuclear Envelope; Nuclear Proteins
PubMed: 31308244
DOI: 10.1242/jcs.229245 -
Cells Dec 2022The nuclear envelope constitutes a selective barrier that segregates chromatin into the nucleus of eukaryotic cells [...].
The nuclear envelope constitutes a selective barrier that segregates chromatin into the nucleus of eukaryotic cells [...].
Topics: Nuclear Envelope; Cell Nucleus; Chromatin; Eukaryotic Cells; Lipids
PubMed: 36552884
DOI: 10.3390/cells11244120 -
Current Opinion in Cell Biology Jun 2021The defining feature of the eukaryotic cell, the nucleus, is bounded by a double envelope. This envelope and the nuclear pores within it play a critical role in... (Review)
Review
The defining feature of the eukaryotic cell, the nucleus, is bounded by a double envelope. This envelope and the nuclear pores within it play a critical role in separating the genome from the cytoplasm. It also presents cells with a challenge. How are cells to remodel the nuclear compartment boundary during mitosis without compromising nuclear function? In the two billion years since the emergence of the first cells with a nucleus, eukaryotes have evolved a range of strategies to do this. At one extreme, the nucleus is disassembled upon entry into mitosis and then reassembled anew in the two daughter cells. At the other, cells maintain an intact nuclear compartment boundary throughout the division process. In this review, we discuss common features of the division process that underpin remodelling mechanisms, the topological challenges involved and speculate on the selective pressures that may drive the evolution of distinct modes of division.
Topics: Cell Nucleus; Cytoplasm; Humans; Mitosis; Nuclear Envelope; Nuclear Pore
PubMed: 33421755
DOI: 10.1016/j.ceb.2020.12.004 -
Current Opinion in Cell Biology Jun 2015Viruses encounter and manipulate almost all aspects of cell structure and metabolism. The nuclear envelope (NE), with central roles in cell structure and genome... (Review)
Review
Viruses encounter and manipulate almost all aspects of cell structure and metabolism. The nuclear envelope (NE), with central roles in cell structure and genome function, acts and is usurped in diverse ways by different viruses. It can act as a physical barrier to infection that must be overcome, as a functional barrier that restricts infection by various mechanisms and must be counteracted or indeed as a positive niche, important or even essential for virus infection or production of progeny virions. This review summarizes virus-host interactions at the NE, highlighting progress in understanding the replication of viruses including HIV-1, Influenza, Herpes Simplex, Adenovirus and Ebola, and molecular insights into hitherto unknown functional pathways at the NE.
Topics: Animals; Humans; Nuclear Envelope; Simplexvirus; Spinal Cord Dorsal Horn; Virus Integration; Virus Replication
PubMed: 26121672
DOI: 10.1016/j.ceb.2015.06.002 -
Aging Cell May 2020The nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the... (Review)
Review
The nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the cytoplasm and the nucleus. The NE is mainly composed of a nuclear lamina and a double membrane connected at specific points where the nuclear pore complexes (NPCs) form. Physiological aging might be generically defined as a functional decline across lifespan observed from the cellular to organismal level. Therefore, during aging and premature aging, several cellular alterations occur, including nuclear-specific changes, particularly, altered nuclear transport, increased genomic instability induced by DNA damage, and telomere attrition. Here, we highlight and discuss proteins associated with nuclear transport dysfunction induced by aging, particularly nucleoporins, nuclear transport factors, and lamins. Moreover, changes in the structure of chromatin and consequent heterochromatin rearrangement upon aging are discussed. These alterations correlate with NE dysfunction, particularly lamins' alterations. Finally, telomere attrition is addressed and correlated with altered levels of nuclear lamins and nuclear lamina-associated proteins. Overall, the identification of molecular mechanisms underlying NE dysfunction, including upstream and downstream events, which have yet to be unraveled, will be determinant not only to our understanding of several pathologies, but as here discussed, in the aging process.
Topics: Animals; Cell Nucleus; Cellular Senescence; Humans; Nuclear Envelope
PubMed: 32291910
DOI: 10.1111/acel.13143 -
Biochemical Society Transactions Aug 2018Morphological abnormalities of the bounding membranes of the nucleus have long been associated with human diseases from cancer to premature aging to neurodegeneration.... (Review)
Review
Morphological abnormalities of the bounding membranes of the nucleus have long been associated with human diseases from cancer to premature aging to neurodegeneration. Studies over the past few decades support that there are both cell intrinsic and extrinsic factors (e.g. mechanical force) that can lead to nuclear envelope 'herniations', a broad catch-all term that reveals little about the underlying molecular mechanisms that contribute to these morphological defects. While there are many genetic perturbations that could ultimately change nuclear shape, here, we focus on a subset of nuclear envelope herniations that likely arise as a consequence of disrupting physiological nuclear membrane remodeling pathways required to maintain nuclear envelope homeostasis. For example, stalling of the interphase nuclear pore complex (NPC) biogenesis pathway and/or triggering of NPC quality control mechanisms can lead to herniations in budding yeast, which are remarkably similar to those observed in human disease models of early-onset dystonia. By also examining the provenance of nuclear envelope herniations associated with emerging nuclear autophagy and nuclear egress pathways, we will provide a framework to help understand the molecular pathways that contribute to nuclear deformation.
Topics: Homeostasis; Humans; Interphase; Nuclear Envelope; Nuclear Pore; Nuclear Proteins; Protein Transport
PubMed: 30026368
DOI: 10.1042/BST20170442