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Nucleus (Austin, Tex.) Jan 2018Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the... (Review)
Review
Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually due to cardiovascular complications. HGPS is caused by a de novo point mutation in the LMNA gene encoding the intermediate filament proteins lamins A and C which are structural components of the nuclear lamina. This mutation leads to the production of a truncated toxic form of lamin A, issued from aberrant splicing and called progerin. Progerin accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. HGPS cells and animal preclinical models have provided insights into the molecular and cellular pathways that underlie the disease and have also highlighted possible mechanisms involved in normal aging. This review reports recent medical advances and treatment approaches for patients affected with HGPS.
Topics: Animals; Cell Nucleus; Humans; Mutation; Progeria
PubMed: 29619863
DOI: 10.1080/19491034.2018.1460045 -
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 -
Nature Cell Biology Jun 2022Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied...
Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism and engineered exogenously by introducing appropriate nuclear localization signals. Our work unveils a mechanism of mechanically induced signalling, probably operating in parallel with others, with potential applicability across signalling pathways.
Topics: Active Transport, Cell Nucleus; Cell Nucleus; Nuclear Pore; Protein Transport; Receptors, Cytoplasmic and Nuclear
PubMed: 35681009
DOI: 10.1038/s41556-022-00927-7 -
Cell Mar 2013The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to... (Review)
Review
The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to an asymmetric position aligned with cell function. We consider the toolbox of proteins that move and anchor the nucleus within the cell and how forces generated by the cytoskeleton are coupled to the nucleus to move it. The significance of proper nuclear positioning is underscored by numerous diseases resulting from genetic alterations in the toolbox proteins. Finally, we discuss how nuclear position may influence cellular organization and signaling pathways.
Topics: Animals; Biomechanical Phenomena; Cell Nucleus; Cells; Cytoskeleton; Humans; Microtubules
PubMed: 23498944
DOI: 10.1016/j.cell.2013.02.031 -
Molecular and Biochemical Parasitology 2016The nucleus is arguably the defining characteristic of eukaryotes, distinguishing their cell organisation from both bacteria and archaea. Though the evolutionary history... (Review)
Review
The nucleus is arguably the defining characteristic of eukaryotes, distinguishing their cell organisation from both bacteria and archaea. Though the evolutionary history of the nucleus remains the subject of debate, its emergence differs from several other eukaryotic organelles in that it appears not to have evolved through symbiosis, but by cell membrane elaboration from an archaeal ancestor. Evolution of the nucleus has been accompanied by elaboration of nuclear structures that are intimately linked with most aspects of nuclear genome function, including chromosome organisation, DNA maintenance, replication and segregation, and gene expression controls. Here we discuss the complexity of the nucleus and its substructures in protozoan eukaryotes, with a particular emphasis on divergent aspects in eukaryotic parasites, which shed light on nuclear function throughout eukaryotes and reveal specialisations that underpin pathogen biology.
Topics: Cell Nucleus; Chromosomes; DNA Replication; Eukaryota; Gene Expression; Gene Expression Regulation; Mitosis
PubMed: 27181562
DOI: 10.1016/j.molbiopara.2016.05.002 -
Nature Apr 2023Interactions between biomolecules underlie all cellular processes and ultimately control cell fate. Perturbation of native interactions through mutation, changes in...
Interactions between biomolecules underlie all cellular processes and ultimately control cell fate. Perturbation of native interactions through mutation, changes in expression levels or external stimuli leads to altered cellular physiology and can result in either disease or therapeutic effects. Mapping these interactions and determining how they respond to stimulus is the genesis of many drug development efforts, leading to new therapeutic targets and improvements in human health. However, in the complex environment of the nucleus, it is challenging to determine protein-protein interactions owing to low abundance, transient or multivalent binding and a lack of technologies that are able to interrogate these interactions without disrupting the protein-binding surface under study. Here, we describe a method for the traceless incorporation of iridium-photosensitizers into the nuclear micro-environment using engineered split inteins. These Ir-catalysts can activate diazirine warheads through Dexter energy transfer to form reactive carbenes within an approximately 10 nm radius, cross-linking with proteins in the immediate micro-environment (a process termed µMap) for analysis using quantitative chemoproteomics. We show that this nanoscale proximity-labelling method can reveal the critical changes in interactomes in the presence of cancer-associated mutations, as well as treatment with small-molecule inhibitors. µMap improves our fundamental understanding of nuclear protein-protein interactions and, in doing so, is expected to have a significant effect on the field of epigenetic drug discovery in both academia and industry.
Topics: Humans; Cell Nucleus; Chromatin; Cross-Linking Reagents; Energy Transfer; Epigenomics; Inteins; Iridium; Mutation; Neoplasms; Photosensitizing Agents; Protein Binding; Protein Interaction Maps
PubMed: 37020029
DOI: 10.1038/s41586-023-05914-y -
Biophysical Journal Nov 2022Several simulation studies have recently appeared in Biophysical Journal that investigate the formation of biomolecular condensates in the nucleus. These structures...
Several simulation studies have recently appeared in Biophysical Journal that investigate the formation of biomolecular condensates in the nucleus. These structures explain a large variety of biological phenomena, from epigenetic inheritance, to enhancer-promoter interactions, to the spatial organization of the entire cell nucleus.
Topics: Chromatin; Computer Simulation; Cell Nucleus
PubMed: 36261037
DOI: 10.1016/j.bpj.2022.10.007 -
Cold Spring Harbor Perspectives in... Aug 2021Viral infection is intrinsically linked to the capacity of the virus to generate progeny. Many DNA and some RNA viruses need to access the nuclear machinery and... (Review)
Review
Viral infection is intrinsically linked to the capacity of the virus to generate progeny. Many DNA and some RNA viruses need to access the nuclear machinery and therefore transverse the nuclear envelope barrier through the nuclear pore complex. Viral genomes then become chromatinized either in their episomal form or upon integration into the host genome. Interactions with host DNA, transcription factors or nuclear bodies mediate their replication. Often interfering with nuclear functions, viruses use nuclear architecture to ensure persistent infections. Discovering these multiple modes of replication and persistence served in unraveling many important nuclear processes, such as nuclear trafficking, transcription, and splicing. Here, by using examples of DNA and RNA viral families, we portray the nucleus with the virus inside.
Topics: Animals; Cell Nucleus; DNA Viruses; Gene Expression Regulation, Viral; Humans; RNA Viruses; Virus Integration
PubMed: 33753405
DOI: 10.1101/cshperspect.a039446 -
Cell Jul 2018Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation....
Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the genome exhibits preferential organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.
Topics: Cell Nucleolus; Cell Nucleus; Chromosome Mapping; Chromosomes; DNA; Eukaryota; Genome; Humans; Structure-Activity Relationship
PubMed: 29887377
DOI: 10.1016/j.cell.2018.05.024 -
Annual Review of Cell and Developmental... Oct 2021The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene... (Review)
Review
The cell nucleus is best known as the container of the genome. Its envelope provides a barrier for passive macromolecule diffusion, which enhances the control of gene expression. As its largest and stiffest organelle, the nucleus also defines the minimal space requirements of a cell. Internal or external pressures that deform a cell to its physical limits cause a corresponding nuclear deformation. Evidence is consolidating that the nucleus, in addition to its genetic functions, serves as a physical sensing device for critical cell body deformation. Nuclear mechanotransduction allows cells to adapt their acute behaviors, mechanical stability, paracrine signaling, and fate to their physical surroundings. This review summarizes the basic chemical and mechanical properties of nuclear components, and how these properties are thought to be utilized for mechanosensing.
Topics: Cell Nucleus; Mechanotransduction, Cellular
PubMed: 34213953
DOI: 10.1146/annurev-cellbio-120319-030049