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Ayantika Sen Gupta, Gaurav Joshi, Sumit Pawar, Kundan Sengupta
Eukaryotic cells have 2 to ​3 discrete nucleoli required for ribosome synthesis. Nucleoli are phase separated nuclear sub-organelles. Here we examined the role of nuclear Lamins and nucleolar factors in modulating the compartmentalization and dynamics of histone 2B (H2B-ECFP) in the nucleolus. Live imaging and Fluorescence Recovery After Photobleaching (FRAP) of labelled H2B, showed that the depletion of Lamin B1, Fibrillarin (FBL) or Nucleostemin (GNL3), enhances H2B-ECFP mobility in the nucleolus. Furthermore, Nucleolin knockdown significantly decreases H2B-ECFP compartmentalization in the nucleolus, while H2B-ECFP residence and mobility in the nucleolus was prolonged upon Nucleolin overexpression...
June 26, 2018: Nucleus
Romina Burla, Mattia La Torre, Chiara Merigliano, Fiammetta Vernì, Isabella Saggio
Progeroid syndromes induced by mutations in lamin A or in its interactors - named progeroid laminopathies - are model systems for the dissection of the molecular pathways causing physiological and premature aging. A large amount of data, based mainly on the Hutchinson Gilford Progeria syndrome (HGPS), one of the best characterized progeroid laminopathy, has highlighted the role of lamins in multiple DNA activities, including replication, repair, chromatin organization and telomere function. On the other hand, the phenotypes generated by mutations affecting genes directly acting on DNA function, as mutations in the helicases WRN and BLM or in the polymerase polδ, share many of the traits of progeroid laminopathies...
June 23, 2018: Nucleus
G Peretto, S Sala, S Benedetti, C Di Resta, L Gigli, M Ferrari, P Della Bella
Cardiac laminopathies, associated with mutations in the LMNA gene, encompass a wide spectrum of clinical manifestations, involving electrical and mechanical alterations of cardiomyocytes. Thus, dilated cardiomyopathy, bradyarrhythmias and atrial or ventricular tachyarrhythmias may occur in a number of combined phenotypes. Nowadays, some attempt has been made to identify clinical predictors for the most life-threatening complications of LMNA-associated heart disease, i.e. sudden cardiac death and end-stage heart failure...
June 21, 2018: Nucleus
Charlotte Capitanchik, Charles Dixon, Selene K Swanson, Laurence Florens, Alastair R W Kerr, Eric C Schirmer
Nuclear envelopathies/laminopathies yield tissue-specific pathologies, yet arise from mutation of ubiquitously-expressed genes. One possible explanation of this tissue specificity is that tissue-specific partners become disrupted from larger complexes, but a little investigated alternate hypothesis is that the mutated proteins themselves have tissue-specific splice variants. Here, we analyze RNA-Seq datasets to identify muscle-specific splice variants of nuclear envelope genes that could be relevant to the study of laminopathies, particularly muscular dystrophies, that are not currently annotated in sequence databases...
June 18, 2018: Nucleus
Cristina Cappelletti, Franco Salerno, Eleonora Canioni, Marina Mora, Renato Mantegazza, Pia Bernasconi, Lorenzo Maggi
Laminopathies are a heterogeneous group of diseases with overlapping phenotypes that are caused by mutations in the nuclear envelope proteins lamin A and C. The most common group of laminopathies affects skeletal and cardiac muscle tissue, and is defined as LMNA-related myopathies (LMNA-RM). In LMNA-RM patients, muscle histological findings are very variable, ranging from mild and unspecific changes to dystrophic features, sometimes with inflammatory evidence. As recently demonstrated in Duchenne muscular dystrophy, we wondered whether in LMNA-RM muscle tissue the genetic defect might determine the activation of an innate immune response, mainly mediated by Toll-like receptors (TLRs), leading to a chronic inflammation and contributing to myofiber necrosis and fibrosis...
June 12, 2018: Nucleus
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January 1, 2018: Nucleus
Pia Bernasconi, Nicola Carboni, Giulia Ricci, Gabriele Siciliano, Luisa Politano, Lorenzo Maggi, Tiziana Mongini, Liliana Vercelli, Carmelo Rodolico, Elena Biagini, Giuseppe Boriani, Lucia Ruggiero, Lucio Santoro, Elisa Schena, Sabino Prencipe, Camilla Evangelisti, Elena Pegoraro, Lucia Morandi, Marta Columbaro, Chiara Lanzuolo, Patrizia Sabatelli, Paola Cavalcante, Cristina Cappelletti, Gisèle Bonne, Antoine Muchir, Giovanna Lattanzi
Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients...
January 1, 2018: Nucleus
Simona Graziano, Ray Kreienkamp, Nuria Coll-Bonfill, Susana Gonzalo
Mammalian nuclei are equipped with a framework of intermediate filaments that function as a karyoskeleton. This nuclear scaffold, formed primarily by lamins (A-type and B-type), maintains the spatial and functional organization of the genome and of sub-nuclear compartments. Over the past decade, a body of evidence has highlighted the significance of these structural nuclear proteins in the maintenance of nuclear architecture and mechanical stability, as well as genome function and integrity. The importance of these structures is now unquestioned given the wide range of degenerative diseases that stem from LMNA gene mutations, including muscular dystrophy disorders, peripheral neuropathies, lipodystrophies, and premature aging syndromes...
January 1, 2018: Nucleus
Agnieszka Madej-Pilarczyk
Emery-Dreifuss muscular dystrophy (EDMD), clinically characterized by scapulo-humero-peroneal muscle atrophy and weakness, multi-joint contractures with spine rigidity and cardiomyopathy with conduction defects, is associated with structural/functional defect of genes that encode the proteins of nuclear envelope, including lamin A and several lamin-interacting proteins. This paper presents clinical aspects of EDMD in context to causative genes, genotype-phenotype correlation and its emplacement within phenotypic spectrum of skeletal muscle diseases associated with envelopathies...
January 1, 2018: Nucleus
Andrea Bianchi, Pierluigi Giuseppe Manti, Federica Lucini, Chiara Lanzuolo
The alteration of the several roles that Lamin A/C plays in the mammalian cell leads to a broad spectrum of pathologies that - all together - are named laminopathies. Among those, the Emery Dreifuss Muscular Dystrophy (EDMD) is of particular interest as, despite the several known mutations of Lamin A/C, the genotype-phenotype correlation still remains poorly understood; this suggests that the epigenetic background of patients might play an important role during the time course of the disease. Historically, both a mechanical role of Lamin A/C and a regulative one have been suggested as the driving force of laminopathies; however, those two hypotheses are not mutually exclusive...
January 1, 2018: Nucleus
Karim Harhouri, Diane Frankel, Catherine Bartoli, Patrice Roll, Annachiara De Sandre-Giovannoli, Nicolas Lévy
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...
January 1, 2018: Nucleus
Sangkyun Cho, Amal Abbas, Jerome Irianto, Irena L Ivanovska, Yuntao Xia, Manu Tewari, Dennis E Discher
Interphase phosphorylation of lamin-A,C depends dynamically on a cell's microenvironment, including the stiffness of extracellular matrix. However, phosphorylation dynamics is poorly understood for diseased forms such as progerin, a permanently farnesylated mutant of LMNA that accelerates aging of stiff and mechanically stressed tissues. Here, fine-excision alignment mass spectrometry (FEA-MS) is developed to quantify progerin and its phosphorylation levels in patient iPS cells differentiated to mesenchymal stem cells (MSCs)...
January 1, 2018: Nucleus
Koichi Utani, Mirit I Aladjem
Since the discovery of a yeast gene silencing modifier (Silent Information Modifier 2, SIR2) and its role in maintaining genomic stability more than two decades ago, SIR2 homologs (sirtuins) were identified in diverse species. Sirtuins are protein deacetylases that play diverse roles in proper cellular metabolism including cell cycle progression and maintenance of genomic stability. In yeast, SIR2 interacts with replication origins and protein complexes that affect both replication origin usage and gene silencing...
January 1, 2018: Nucleus
Corinne Vigouroux, Anne-Claire Guénantin, Camille Vatier, Emilie Capel, Caroline Le Dour, Pauline Afonso, Guillaume Bidault, Véronique Béréziat, Olivier Lascols, Jacqueline Capeau, Nolwenn Briand, Isabelle Jéru
Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure...
January 1, 2018: Nucleus
Cristina Guillín-Amarelle, Antía Fernández-Pombo, Sofía Sánchez-Iglesias, David Araújo-Vilar
The nuclear lamina is a complex reticular structure that covers the inner face of the nucleus membrane in metazoan cells. It is mainly formed by intermediate filaments called lamins, and exerts essential functions to maintain the cellular viability. Lamin A/C provides mechanical steadiness to the nucleus and regulates genetic machinery. Laminopathies are tissue-specific or systemic disorders caused by variants in LMNA gene (primary laminopathies) or in other genes encoding proteins which are playing some role in prelamin A maturation or in lamin A/C function (secondary laminopathies)...
January 1, 2018: Nucleus
Ryszard Rzepecki, Yosef Gruenbaum
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...
January 1, 2018: Nucleus
Nolwenn Briand, Philippe Collas
The nuclear lamina contributes to the regulation of gene expression and to chromatin organization. Mutations in A-type nuclear lamins cause laminopathies, some of which are associated with a loss of heterochromatin at the nuclear periphery. Until recently however, little if any information has been provided on where and how lamin A interacts with the genome and on how disease-causing lamin A mutations may rearrange genome conformation. Here, we review aspects of nuclear lamin association with the genome. We highlight recent evidence of reorganization of lamin A-chromatin interactions in cellular models of laminopathies, and implications on the 3-dimensional rearrangement of chromatin in these models, including patient cells...
January 1, 2018: Nucleus
Shalaka Chitale, Holger Richly
The integrity of the genome is maintained by specific DNA repair pathways. The main pathway removing DNA lesions induced by exposure to UV light is nucleotide excision repair (NER). The DNA damage response at chromatin is accompanied by the recruitment of DNA repair factors to the lesion site and the deposition of specific histone marks. The function of these histone marks in NER stays for the most part elusive. We have recently reported that the methyltransferase MMSET catalyzes the dimethylation of histone H4 at lysine 20 (H4K20me2) at the lesion site...
January 1, 2018: Nucleus
Mohammad Soheilypour, Mohammad R K Mofrad
Despite extensive research on how mRNAs are quality controlled prior to export into the cytoplasm, the exact underlying mechanisms are still under debate. Specifically, it is unclear how quality control proteins at the entry of the nuclear pore complex (NPC) distinguish normal and aberrant mRNAs. While some of the involved components are suggested to act as switches and recruit different factors to normal versus aberrant mRNAs, some experimental and computational evidence suggests that the combined effect of the regulated stochastic interactions between the involved components could potentially achieve an efficient quality control of mRNAs...
January 1, 2018: Nucleus
David Lando, Tim J Stevens, Srinjan Basu, Ernest D Laue
Single-cell chromosome conformation capture approaches are revealing the extent of cell-to-cell variability in the organization and packaging of genomes. These single-cell methods, unlike their multi-cell counterparts, allow straightforward computation of realistic chromosome conformations that may be compared and combined with other, independent, techniques to study 3D structure. Here we discuss how single-cell Hi-C and subsequent 3D genome structure determination allows comparison with data from microscopy...
January 1, 2018: Nucleus
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