Authors: Guilherme Pedreira de Freitas Nader, Sonia Agüera-Gonzalez, Fiona Routet...

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

Authors: Celine M Denais, Rachel M Gilbert, Philipp Isermann...

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

Review

Authors: Stefan Petrovic, George W Mobbs, Christopher J Bley...

The nucleus, a genome-containing organelle eponymous of eukaryotes, is enclosed by a double membrane continuous with the endoplasmic reticulum. The nuclear pore complex (NPC) is an ∼110-MDa, ∼1000-protein channel that selectively transports macromolecules across the nuclear envelope and thus plays a central role in the regulated flow of genetic information from transcription to translation. Its size, complexity, and flexibility have hindered determination of atomistic structures of intact NPCs. Recent studies have overcome these hurdles by combining biochemical reconstitution and docking of high-resolution structures of NPC subcomplexes into cryo-electron tomographic reconstructions with biochemical and physiological validation. Here, we provide an overview of the near-atomic composite structure of the human NPC, a milestone toward unlocking a molecular understanding of mRNA export, NPC-associated diseases, and viral host-pathogen interactions, serving as a paradigm for studying similarly large complexes.

Topics: Humans; Nuclear Pore; Active Transport, Cell Nucleus; Cell Nucleus; Endoplasmic Reticulum; Eukaryota; Nuclear Envelope

PubMed: 36096637
DOI: 10.1101/cshperspect.a041264

Authors: Birthe Fahrenkrog, Susan M Gasser

Topics: Nuclear Envelope; Nuclear Pore; Cell Nucleus

PubMed: 38013590
DOI: 10.1002/1873-3468.14769

Review

Authors: Bernhard Hampoelz, Janina Baumbach

The nuclear envelope (NE) protects but also organizes the eukaryotic genome. In this review we will discuss recent literature on how the NE disassembles and reassembles, how it varies in surface area and protein composition and how this translates into chromatin organization and gene expression in the context of animal development.

Topics: Animals; Nuclear Envelope; Eukaryotic Cells; Genome

PubMed: 35249812
DOI: 10.1016/j.semcdb.2022.02.028

Review

Authors: Thomas Hennig, Peter O'Hare

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

Review

Authors: Maria Alvarado-Kristensson, Catalina Ana Rosselló

The formation of the nuclear envelope and the subsequent compartmentalization of the genome is a defining feature of eukaryotes. Traditionally, the nuclear envelope was purely viewed as a physical barrier to preserve genetic material in eukaryotic cells. However, in the last few decades, it has been revealed to be a critical cellular component in controlling gene expression and has been implicated in several human diseases. In cancer, the relevance of the cell nucleus was first reported in the mid-1800s when an altered nuclear morphology was observed in tumor cells. This review aims to give a current and comprehensive view of the role of the nuclear envelope on cancer first by recapitulating the changes of the nuclear envelope during cell division, second, by reviewing the role of the nuclear envelope in cell cycle regulation, signaling, and the regulation of the genome, and finally, by addressing the nuclear envelope link to cell migration and metastasis and its use in cancer prognosis.

Topics: Animals; Cell Cycle; Cell Movement; Humans; Neoplasms; Nuclear Envelope

PubMed: 31137762
DOI: 10.3390/ijms20102586

Authors: Wei Xie, Brian Burke

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

Review

Authors: David J Thaller, C Patrick Lusk

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

Review

Authors: Filipa Martins, Jéssica Sousa, Cátia D Pereira...

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