Oxydative stress alters nuclear shape through lamins dysregulation

Barascu, Aurélia; Chalony, Catherine Le; Pennarun, Gaëlle; Genet, Diane; Zaarour, Nancy; Bertrand, Pascale

doi:10.4161/nucl.21674

Cited by 29 publications

(28 citation statements)

References 59 publications

(95 reference statements)

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“…The telomere mobility is increased in cells lacking A-type lamins, is reduced in HGPS cells [312]. An oxidative stress including ROS overproduction and a reduced level of antioxidant defenses is encountered in the two types of progeroid syndromes, laminopathies and DNA damage response defects [313][314][315][316] (see below Section 3.8). Upon oxidative stress, TERT can shuttle from the nucleus to the mitochondria, where it protects mitochondrial function, decreases mitochondrial ROS levels and prevents nuclear DNA damage, but does not correct telomere shortening [317,318].…”

Section: Telomerase Complex Defects In Laminopathic Cellsmentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.

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Section: Telomerase Complex Defects In Laminopathic Cellsmentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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“…[13][14][15][16][17][18][19][20][21][22][23].The cell nuclei are reportedly involved in several aspects of intra-cellular dynamics, such as the oscillation, rotation and deformation driven by the dynamics of the cytoskeleton including microtubule and actin networks [24][25][26][27][28][29][30][31][32][33][34][35][36][37]. The dynamics of nuclei often affect the positioning and structures of intra-nuclear architectures and gene expression via interactions between the chromosomes and the nuclear periphery [24][25][26][27][28][29][30][31][32][33][34][35][37][38][39][40][41]. Moreover, the membrane proteins such as Lamin A, B, C, and Lamin receptors anchor heterochromatin to the nuclear periphery [10,11,[42][43]…”

mentioning

confidence: 99%

Nuclear dynamical deformation induced hetero- and euchromatin positioning

Awazu

2015

Phys. Rev. E

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We studied the role of active deformation dynamics in cell nuclei in chromatin positioning. Model chains containing two types of regions, with high (euchromatic) or low (heterochromatic) mobility, were confined in a pulsating container simulating a nucleus showing dynamic deformations. Brownian dynamic simulations show that the positioning of low mobility regions changes from sites near the periphery to the center if the affinity between these regions and the container periphery disappears. The former and latter positionings are similar to the "conventional" and "inverted" chromatin positionings in nuclei of normal differentiated cells and cells lacking Lamin-related proteins. Additionally, nuclear dynamical deformation played essential roles in "inverted" chromatin positioning.

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“…Modifications to quantitative histological parameters, such as the nuclear alterations observed in pathological perinatal clones, offered further evidence that they suffered from abnormal liver physiology and metabolism. Indeed, the size and shape of the interphase nucleus are closely dependent on cell size, function and metabolism and can be modified by ageing, oxidative stress and pathology373839. Steatosis may also have contributed to the nuclear alterations we observed, since lipid vesicles compress the nucleus at the periphery of the hepatocyte, leading to its deformation.…”

Section: Discussionmentioning

confidence: 85%

Altered DNA methylation associated with an abnormal liver phenotype in a cattle model with a high incidence of perinatal pathologies

Kiefer

Jouneau

Campion

et al. 2016

Sci Rep

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Cloning enables the generation of both clinically normal and pathological individuals from the same donor cells, and may therefore be a DNA sequence-independent driver of phenotypic variability. We took advantage of cattle clones with identical genotypes but different developmental abilities to investigate the role of epigenetic factors in perinatal mortality, a complex trait with increasing prevalence in dairy cattle. We studied livers from pathological clones dying during the perinatal period, clinically normal adult clones with the same genotypes as perinatal clones and conventional age-matched controls. The livers from deceased perinatal clones displayed histological lesions, modifications to quantitative histomorphometric and metabolic parameters such as glycogen storage and fatty acid composition, and an absence of birth-induced maturation. In a genome-wide epigenetic analysis, we identified DNA methylation patterns underlying these phenotypic alterations and targeting genes relevant to liver metabolism, including the type 2 diabetes gene TCF7L2. The adult clones were devoid of major phenotypic and epigenetic abnormalities in the liver, ruling out the effects of genotype on the phenotype observed. These results thus provide the first demonstration of a genome-wide association between DNA methylation and perinatal mortality in cattle, and highlight epigenetics as a driving force for phenotypic variability in farmed animals.

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Oxydative stress alters nuclear shape through lamins dysregulation

Cited by 29 publications

References 59 publications

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Nuclear dynamical deformation induced hetero- and euchromatin positioning

Altered DNA methylation associated with an abnormal liver phenotype in a cattle model with a high incidence of perinatal pathologies

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