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Cold Spring Harbor Perspectives in... Feb 2022Lamins interact with a host of nuclear membrane proteins, transcription factors, chromatin regulators, signaling molecules, splicing factors, and even chromatin itself... (Review)
Review
Lamins interact with a host of nuclear membrane proteins, transcription factors, chromatin regulators, signaling molecules, splicing factors, and even chromatin itself to form a nuclear subcompartment, the nuclear lamina, that is involved in a variety of cellular processes such as the governance of nuclear integrity, nuclear positioning, mitosis, DNA repair, DNA replication, splicing, signaling, mechanotransduction and -sensation, transcriptional regulation, and genome organization. Lamins are the primary scaffold for this nuclear subcompartment, but interactions with lamin-associated peptides in the inner nuclear membrane are self-reinforcing and mutually required. Lamins also interact, directly and indirectly, with peripheral heterochromatin domains called lamina-associated domains (LADs) and help to regulate dynamic 3D genome organization and expression of developmentally regulated genes.
Topics: Cell Nucleus; Chromatin; Lamins; Mechanotransduction, Cellular; Nuclear Envelope; Nuclear Lamina
PubMed: 34400553
DOI: 10.1101/cshperspect.a040113 -
Annual Review of Pathology Jan 2022The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding... (Review)
Review
The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding protein components of the lamina and these other nuclear envelope substructures. Mutations in the single gene encoding lamin A and C, which are expressed in most differentiated somatic cells, cause diseases affecting striated muscle, adipose tissue, peripheral nerve, and multiple systems with features of accelerated aging. Mutations in genes encoding other nuclear envelope proteins also cause an array of diseases that selectively affect different tissues or organs. In some instances, the molecular and cellular consequences of laminopathy-causing mutations are known. However, even when these are understood, mechanisms explaining specific tissue or organ pathology remain enigmatic. Current mechanistic hypotheses focus on how alterations in the nuclear envelope may affect gene expression, including via the regulation of signaling pathways, or cellular mechanics, including responses to mechanical stress.
Topics: Humans; Lamin Type A; Laminopathies; Mutation; Signal Transduction
PubMed: 34672689
DOI: 10.1146/annurev-pathol-042220-034240 -
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 -
Nucleus (Austin, Tex.) 2018
Topics: Heart Diseases; Humans; Lamin Type A; Musculoskeletal Diseases; Mutation
PubMed: 30719953
DOI: 10.1080/19491034.2018.1515606 -
Cold Spring Harbor Perspectives in... Apr 2010A- and B-type lamins are the major intermediate filaments of the nucleus. Lamins engage in a plethora of stable and transient interactions, near the inner nuclear... (Review)
Review
A- and B-type lamins are the major intermediate filaments of the nucleus. Lamins engage in a plethora of stable and transient interactions, near the inner nuclear membrane and throughout the nucleus. Lamin-binding proteins serve an amazingly diverse range of functions. Numerous inner-membrane proteins help anchor lamin filaments to the nuclear envelope, serving as part of the nuclear "lamina" network that is essential for nuclear architecture and integrity. Certain lamin-binding proteins of the inner membrane bind partners in the outer membrane and mechanically link lamins to the cytoskeleton. Inside the nucleus, lamin-binding proteins appear to serve as the "adaptors" by which the lamina organizes chromatin, influences gene expression and epigenetic regulation, and modulates signaling pathways. Transient interactions of lamins with key components of the transcription and replication machinery may provide an additional level of regulation or support to these essential events.
Topics: Animals; Chromatin; Cytoskeleton; DNA-Binding Proteins; Lamins; Mice; Nuclear Envelope
PubMed: 20452940
DOI: 10.1101/cshperspect.a000554 -
Nucleus (Austin, Tex.) Jan 2018Lamins are evolutionarily conserved nuclear intermediate filament proteins. They provide structural support for the nucleus and help regulate many other nuclear... (Review)
Review
Lamins are evolutionarily conserved nuclear intermediate filament proteins. They provide structural support for the nucleus and help regulate many other nuclear activities. Mutations in human lamin genes, and especially in the LMNA gene, cause numerous diseases, termed laminopathies, including muscle, cardiac, metabolic, neuronal and early aging diseases. Most laminopathies arise from autosomal dominant missense mutations. Many of the mutant residues are conserved in the lamin genes of the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Our current understanding of the mechanisms leading to these diseases is mostly based on patients cell lines and animal models including C. elegans and D. melanogaster. The simpler lamin system and the powerful genetic tools offered by these invertebrate organisms greatly contributed to such studies. Here we provide an overview of the studies of laminopathies in Drosophila and C. elegans models.
Topics: Animals; Caenorhabditis elegans; Disease Models, Animal; Drosophila melanogaster; Humans; Lamins; Musculoskeletal Diseases; Mutation
PubMed: 29557730
DOI: 10.1080/19491034.2018.1454166 -
Cells May 2020Mechanotransduction translates forces into biological responses and regulates cell functionalities. It is implicated in several diseases, including laminopathies which... (Review)
Review
Mechanotransduction translates forces into biological responses and regulates cell functionalities. It is implicated in several diseases, including laminopathies which are pathologies associated with mutations in lamins and lamin-associated proteins. These pathologies affect muscle, adipose, bone, nerve, and skin cells and range from muscular dystrophies to accelerated aging. Although the exact mechanisms governing laminopathies and gene expression are still not clear, a strong correlation has been found between cell functionality and nuclear behavior. New theories base on the direct effect of external force on the genome, which is indeed sensitive to the force transduced by the nuclear lamina. Nuclear lamina performs two essential functions in mechanotransduction pathway modulating the nuclear stiffness and governing the chromatin remodeling. Indeed, A-type lamin mutation and deregulation has been found to affect the nuclear response, altering several downstream cellular processes such as mitosis, chromatin organization, DNA replication-transcription, and nuclear structural integrity. In this review, we summarize the recent findings on the molecular composition and architecture of the nuclear lamina, its role in healthy cells and disease regulation. We focus on A-type lamins since this protein family is the most involved in mechanotransduction and laminopathies.
Topics: Animals; Humans; Lamin Type A; Laminopathies; Mechanotransduction, Cellular; Mutation; Protein Binding
PubMed: 32456328
DOI: 10.3390/cells9051306 -
The Journal of Cell Biology Jan 2024Mutations in genes encoding nuclear lamins cause diseases called laminopathies. In this issue, Hasper et al. (https://doi.org/10.1083/jcb.202307049) show that lamin A/C...
Mutations in genes encoding nuclear lamins cause diseases called laminopathies. In this issue, Hasper et al. (https://doi.org/10.1083/jcb.202307049) show that lamin A/C and the prelamin A variant in Hutchinson-Gilford progeria syndrome have relatively long lifetimes in affected tissues.
Topics: Humans; Lamins; Lamin Type A; Nuclear Lamina; Progeria
PubMed: 38078930
DOI: 10.1083/jcb.202311193 -
Current Opinion in Cell Biology Feb 2021Intermediate filaments (IFs) are key players in multiple cellular processes throughout human tissues. Their biochemical and structural properties are important for... (Review)
Review
Intermediate filaments (IFs) are key players in multiple cellular processes throughout human tissues. Their biochemical and structural properties are important for understanding filament assembly mechanisms, for interactions between IFs and binding partners, and for developing pharmacological agents that target IFs. IF proteins share a conserved coiled-coil central-rod domain flanked by variable N-terminal 'head' and C-terminal 'tail' domains. There have been several recent advances in our understanding of IF structure from the study of keratins, glial fibrillary acidic protein, and lamin. These include discoveries of (i) a knob-pocket tetramer assembly mechanism in coil 1B; (ii) a lamin-specific coil 1B insert providing a one-half superhelix turn; (iii) helical, yet flexible, linkers within the rod domain; and (iv) the identification of coil 2B residues required for mature filament assembly. Furthermore, the head and tail domains of some IFs contain low-complexity aromatic-rich kinked segments, and structures of IFs with binding partners show electrostatic surfaces are a major contributor to complex formation. These new data advance the connection between IF structure, pathologic mutations, and clinical diseases in humans.
Topics: Amino Acid Sequence; Animals; Cytoskeleton; Humans; Intermediate Filament Proteins; Intermediate Filaments; Lamins; Models, Molecular; Mutation
PubMed: 33190098
DOI: 10.1016/j.ceb.2020.10.001 -
Gastroenterology May 2018The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and... (Review)
Review
The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies.
Topics: Animals; Cytoskeleton; Gastrointestinal Diseases; Genome; Humans; Lamins; Liver; Mice; Nuclear Lamina; Pancreas
PubMed: 29549040
DOI: 10.1053/j.gastro.2018.03.026