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Nucleus (Austin, Tex.) Apr 2016Chromosome ends are complex structures, which require a panel of factors for their elongation, replication, and protection. We describe here the mechanics of mammalian... (Review)
Review
Chromosome ends are complex structures, which require a panel of factors for their elongation, replication, and protection. We describe here the mechanics of mammalian telomeres, dynamics and maintainance in relation to lamins. Multiple biochemical connections, including association of telomeres to the nuclear envelope and matrix, of telomeric proteins to lamins, and of lamin-associated proteins to chromosome ends, underline the interplay between lamins and telomeres. Paths toward senescence, such as defective telomere replication, altered heterochromatin organization, and impaired DNA repair, are common to lamins' and telomeres' dysfunction. The convergence of phenotypes can be interpreted through a model of dynamic, lamin-controlled functional platforms dedicated to the function of telomeres as fragile sites. The features of telomeropathies and laminopathies, and of animal models underline further overlapping aspects, including the alteration of stem cell compartments. We expect that future studies of basic biology and on aging will benefit from the analysis of this telomere-lamina interplay.
Topics: Animals; DNA Damage; DNA Replication; Disease; Humans; Lamins; Phenotype; Telomere
PubMed: 27116558
DOI: 10.1080/19491034.2016.1179409 -
European Journal of Cell Biology Nov 2016Morphological changes in the size and shape of the nucleus are highly prevalent in cancer, but the underlying molecular mechanisms and the functional relevance remain... (Review)
Review
Morphological changes in the size and shape of the nucleus are highly prevalent in cancer, but the underlying molecular mechanisms and the functional relevance remain poorly understood. Nuclear envelope proteins, which can modulate nuclear shape and organization, have emerged as key components in a variety of signalling pathways long implicated in tumourigenesis and metastasis. The expression of nuclear envelope proteins is altered in many cancers, and changes in levels of nuclear envelope proteins lamins A and C are associated with poor prognosis in multiple human cancers. In this review we highlight the role of the nuclear envelope in different processes important for tumour initiation and cancer progression, with a focus on lamins A and C. Lamin A/C controls many cellular processes with key roles in cancer, including cell invasion, stemness, genomic stability, signal transduction, transcriptional regulation, and resistance to mechanical stress. In addition, we discuss potential mechanisms mediating the changes in lamin levels observed in many cancers. A better understanding of cause-and-effect relationships between lamin expression and tumour progression could reveal important mechanisms for coordinated regulation of oncogenic processes, and indicate therapeutic vulnerabilities that could be exploited for improved patient outcome.
Topics: Animals; Gene Expression Regulation, Neoplastic; Humans; Lamin Type A; Lamins; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasms; Nuclear Envelope; Signal Transduction
PubMed: 27397692
DOI: 10.1016/j.ejcb.2016.06.007 -
Expert Reviews in Molecular Medicine Jul 2013Nuclear envelope spectrin-repeat proteins (Nesprins), are a novel family of nuclear and cytoskeletal proteins with rapidly expanding roles as intracellular scaffolds and... (Review)
Review
Nuclear envelope spectrin-repeat proteins (Nesprins), are a novel family of nuclear and cytoskeletal proteins with rapidly expanding roles as intracellular scaffolds and linkers. Originally described as proteins that localise to the nuclear envelope (NE) and establish nuclear-cytoskeletal connections, nesprins have now been found to comprise a diverse spectrum of tissue specific isoforms that localise to multiple sub-cellular compartments. Here, we describe how nesprins are necessary in maintaining cellular architecture by acting as essential scaffolds and linkers at both the NE and other sub-cellular domains. More importantly, we speculate how nesprin mutations may disrupt tissue specific nesprin scaffolds and explain the tissue specific nature of many nesprin-associated diseases, including laminopathies.
Topics: Animals; Humans; Lamins; Nuclear Envelope; Nuclear Proteins; Organ Specificity
PubMed: 23830188
DOI: 10.1017/erm.2013.6 -
Journal of Experimental & Clinical... Sep 2022Lamins, key nuclear lamina components, have been proposed as candidate risk biomarkers in different types of cancer but their accuracy is still debated. AKTIP is a...
BACKGROUND
Lamins, key nuclear lamina components, have been proposed as candidate risk biomarkers in different types of cancer but their accuracy is still debated. AKTIP is a telomeric protein with the property of being enriched at the nuclear lamina. AKTIP has similarity with the tumor susceptibility gene TSG101. AKTIP deficiency generates genome instability and, in p53 mice, the reduction of the mouse counterpart of AKTIP induces the exacerbation of lymphomas. Here, we asked whether the distribution of AKTIP is altered in cancer cells and whether this is associated with alterations of lamins.
METHODS
We performed super-resolution imaging, quantification of lamin expression and nuclear morphology on HeLa, MCF7, and A549 tumor cells, and on non-transformed fibroblasts from healthy donor and HGPS (LMNA c.1824C > T p.Gly608Gly) and EDMD2 (LMNA c.775 T > G) patients. As proof of principle model combining a defined lamin alteration with a tumor cell setting, we produced HeLa cells exogenously expressing the HGPS lamin mutant progerin that alters nuclear morphology.
RESULTS
In HeLa cells, AKTIP locates at less than 0.5 µm from the nuclear rim and co-localizes with lamin A/C. As compared to HeLa, there is a reduced co-localization of AKTIP with lamin A/C in both MCF7 and A549. Additionally, MCF7 display lower amounts of AKTIP at the rim. The analyses in non-transformed fibroblasts show that AKTIP mislocalizes in HGPS cells but not in EDMD2. The integrated analysis of lamin expression, nuclear morphology, and AKTIP topology shows that positioning of AKTIP is influenced not only by lamin expression, but also by nuclear morphology. This conclusion is validated by progerin-expressing HeLa cells in which nuclei are morphologically altered and AKTIP is mislocalized.
CONCLUSIONS
Our data show that the combined alteration of lamin and nuclear morphology influences the localization of the tumor-associated factor AKTIP. The results also point to the fact that lamin alterations per se are not predictive of AKTIP mislocalization, in both non-transformed and tumor cells. In more general terms, this study supports the thesis that a combined analytical approach should be preferred to predict lamin-associated changes in tumor cells. This paves the way of next translational evaluation to validate the use of this combined analytical approach as risk biomarker.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis Regulatory Proteins; Fibroblasts; HeLa Cells; Humans; Lamin Type A; Mice; Progeria; Telomere
PubMed: 36096808
DOI: 10.1186/s13046-022-02480-5 -
Journal of Structural Biology Jan 2012The nuclear lamina is a protein meshwork that lines the nuclear envelope in metazoan cells. It is composed largely of a polymeric assembly of lamins, which comprise a... (Review)
Review
The nuclear lamina is a protein meshwork that lines the nuclear envelope in metazoan cells. It is composed largely of a polymeric assembly of lamins, which comprise a distinct sequence homology class of the intermediate filament protein family. On the basis of its structural properties, the lamina originally was proposed to provide scaffolding for the nuclear envelope and to promote anchoring of chromatin and nuclear pore complexes at the nuclear surface. This viewpoint has expanded greatly during the past 25 years, with a host of surprising new insights on lamina structure, molecular composition and functional attributes. It has been established that the self-assembly properties of lamins are very similar to those of cytoplasmic intermediate filament proteins, and that the lamin polymer is physically associated with components of the cytoplasmic cytoskeleton and with a multitude of chromatin and inner nuclear membrane proteins. Cumulative evidence points to an important role for the lamina in regulating signaling and gene activity, and in mechanically coupling the cytoplasmic cytoskeleton to the nucleus. The significance of the lamina has been vaulted to the forefront by the discovery that mutations in lamins and lamina-associated polypeptides lead to an array of human diseases. A key future challenge is to understand how the lamina integrates pathways for mechanics and signaling at the molecular level. Understanding the structure of the lamina from the atomic to supramolecular levels will be essential for achieving this goal.
Topics: Animals; Cell Nucleus; Chromatin; Cytoskeleton; Humans; Intermediate Filament Proteins; Lamins; Microscopy, Fluorescence; Models, Molecular; Mutation; Nuclear Envelope; Nuclear Lamina; Nuclear Pore
PubMed: 22126840
DOI: 10.1016/j.jsb.2011.11.007 -
BMB Reports Jul 2018Lamin A and its alternative splicing product Lamin C are the key intermediate filaments (IFs) of the inner nuclear membrane intermediate filament. Lamin A/C forms the... (Review)
Review
Lamin A and its alternative splicing product Lamin C are the key intermediate filaments (IFs) of the inner nuclear membrane intermediate filament. Lamin A/C forms the inner nuclear mesh with Lamin B and works as a frame with a nuclear shape. In addition to supporting the function of nucleus, nuclear lamins perform important roles such as holding the nuclear pore complex and chromatin. However, mutations on the Lamin A or Lamin B related proteins induce various types of human genetic disorders and diseases including premature aging syndromes, muscular dystrophy, lipodystrophy and neuropathy. In this review, we briefly overview the relevance of genetic mutations of Lamin A, human disorders and laminopathies. We also discuss a mouse model for genetic diseases. Finally, we describe the current treatment for laminopathies. [BMB Reports 2018; 51(7): 327-337].
Topics: Animals; Disease Models, Animal; Enzyme Inhibitors; Humans; Lamin Type A; Lipodystrophy; Muscular Dystrophies; Mutation; Progeria
PubMed: 29764566
DOI: 10.5483/bmbrep.2018.51.7.113 -
Molecular Biology of the Cell Feb 2023The nuclear lamina serves important roles in chromatin organization and structural support, and lamina mutations can result in laminopathies. Less is known about how...
The nuclear lamina serves important roles in chromatin organization and structural support, and lamina mutations can result in laminopathies. Less is known about how nuclear lamina structure changes during cellular differentiation-changes that may influence gene regulation. We examined the structure and dynamics of the nuclear lamina in human-induced pluripotent stem cells (iPSCs) and differentiated germ layer cells, focusing on lamin B1. We report that lamin B1 dynamics generally increase as iPSCs differentiate, especially in mesoderm and ectoderm, and that lamin B receptor (LBR) partially redistributes from the nucleus to cytoplasm in mesoderm. Knocking down LBR in iPSCs led to an increase in lamin B1 dynamics, a change that was not observed for ELYS, emerin, or lamin B2 knockdown. LBR knockdown also affected expression of differentiation markers. These data suggest that differentiation-dependent tethering of lamin B1 either directly by LBR or indirectly via LBR-chromatin associations impacts gene expression.
Topics: Humans; Lamin Type A; Lamin Type B; Cell Nucleus; Cell Differentiation; Nuclear Envelope; Lamin B Receptor
PubMed: 36598800
DOI: 10.1091/mbc.E22-04-0137 -
Open Biology Nov 2015The main functions of lamins are their mechanical and structural roles as major building blocks of the karyoskeleton. They are also involved in chromatin structure... (Review)
Review
The main functions of lamins are their mechanical and structural roles as major building blocks of the karyoskeleton. They are also involved in chromatin structure regulation, gene expression, intracellular signalling pathway modulation and development. All essential lamin functions seem to depend on their capacity for assembly or disassembly after the receipt of specific signals, and after specific, selective and precisely regulated interactions through their various domains. Reversible phosphorylation of lamins is crucial for their functions, so it is important to understand how lamin polymerization and interactions are modulated, and which sequences may undergo such modifications. This review combines experimental data with results of our in silico analyses focused on lamin phosphorylation in model organisms to show the presence of evolutionarily conserved sequences and to indicate specific in vivo phosphorylations that affect particular functions.
Topics: Amino Acid Sequence; Animals; Humans; Lamins; Molecular Sequence Data; Phosphorylation; Protein Processing, Post-Translational
PubMed: 26581574
DOI: 10.1098/rsob.150094 -
EMBO Reports Aug 2020The nuclear lamina is essential for the structural integration of the nuclear envelope. Nuclear envelope rupture and chromatin externalization is a hallmark of the...
The nuclear lamina is essential for the structural integration of the nuclear envelope. Nuclear envelope rupture and chromatin externalization is a hallmark of the formation of neutrophil extracellular traps (NETs). NET release was described as a cellular lysis process; however, this notion has been questioned recently. Here, we report that during NET formation, nuclear lamin B is not fragmented by destructive proteolysis, but rather disassembled into intact full-length molecules. Furthermore, we demonstrate that nuclear translocation of PKCα, which serves as the kinase to induce lamin B phosphorylation and disassembly, results in nuclear envelope rupture. Decreasing lamin B phosphorylation by PKCα inhibition, genetic deletion, or by mutating the PKCα consensus sites on lamin B attenuates extracellular trap formation. In addition, strengthening the nuclear envelope by lamin B overexpression attenuates NET release in vivo and reduces levels of NET-associated inflammatory cytokines in UVB-irradiated skin of lamin B transgenic mice. Our findings advance the mechanistic understanding of NET formation by showing that PKCα-mediated lamin B phosphorylation drives nuclear envelope rupture for chromatin release in neutrophils.
Topics: Animals; Lamin Type A; Lamin Type B; Mice; Nuclear Envelope; Nuclear Lamina; Phosphorylation; Protein Kinase C-alpha
PubMed: 32537912
DOI: 10.15252/embr.201948779 -
Genes & Development Feb 2015The intermediate filament proteins, A- and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while... (Review)
Review
The intermediate filament proteins, A- and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a "mechanostat" that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced "inside-out signaling" through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues.
Topics: Animals; Cell Movement; Extracellular Matrix; Gene Expression Regulation; Humans; Lamins; Mechanotransduction, Cellular; Mutation
PubMed: 25644599
DOI: 10.1101/gad.255968.114