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Review
. 2021 Jul 6;22(14):7281.
doi: 10.3390/ijms22147281.

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

Benoit R Gauthier  1   2 , Valentine Comaills  1
Affiliations
Review

Nuclear Envelope Integrity in Health and Disease: Consequences on Genome Instability and Inflammation

Benoit R Gauthier et al. Int J Mol Sci. .

Abstract

The dynamic nature of the nuclear envelope (NE) is often underestimated. The NE protects, regulates, and organizes the eukaryote genome and adapts to epigenetic changes and to its environment. The NE morphology is characterized by a wide range of diversity and abnormality such as invagination and blebbing, and it is a diagnostic factor for pathologies such as cancer. Recently, the micronuclei, a small nucleus that contains a full chromosome or a fragment thereof, has gained much attention. The NE of micronuclei is prone to collapse, leading to DNA release into the cytoplasm with consequences ranging from the activation of the cGAS/STING pathway, an innate immune response, to the creation of chromosomal instability. The discovery of those mechanisms has revolutionized the understanding of some inflammation-related diseases and the origin of complex chromosomal rearrangements, as observed during the initiation of tumorigenesis. Herein, we will highlight the complexity of the NE biology and discuss the clinical symptoms observed in NE-related diseases. The interplay between innate immunity, genomic instability, and nuclear envelope leakage could be a major focus in future years to explain a wide range of diseases and could lead to new classes of therapeutics.

Keywords: cGAS/STING; cancer; chromosomal instability; envelopathy; inflammation; lipodystrophy; neuropathy; nuclear envelope; nuclear envelope disruption.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nuclear envelope composition and organization. (A). The nucleus is surrounded by the nuclear envelope (NE). The Outer Nuclear Membrane (ONM) is continuous with the endoplasmic reticulum. The nuclear pore complex (NPC) regulates the export and import between the nucleus and the cytoplasm. The genome is organized in different compartments: euchromatin, heterochromatin, and nucleolus. (B). Structure of lamin layers in the Inner Nuclear Membrane (INM). (C). The NE is composed of a lipid bilayer anchored by several proteins forming the lamin-associated protein, the LINC complex, and by the lamins. The NE proteins regulate gene organization with the Lamin-Associated Domain (LAD).
Figure 2
Figure 2
Different nuclear abnormalities. (A) Classical cells have one single round nucleus that contains a diploid genome (2N). (B) Cells such as neutrophils possess multi-lobar nucleus. (C,D) Polyploid cells (>4N) can either have two or more separated nuclei or one enlarged nucleus. (E) Some cells can have a smaller nucleus, which is called a micronucleus, in their cytoplasm. Micronuclei contain a full chromosome or a piece thereof. (F) Nuclei can also display blebbing characterized by an outward extension of the nuclear envelope (NE). (G). In addition, cancer cells can show abnormalities such as NE invagination, loosen heterochromatin as a consequence in changes in DNA compaction as well as a single and bigger nucleolus, which is called a macronucleolus.
Figure 3
Figure 3
Example of cells with abnormal nuclear envelope. (A). MDA-MB-231 and SKBR3 breast cancer cells presenting invaginations, twisted nuclei, and micronuclei (white arrow). (B). The breast epithelial cell line MCF10A enters in Epithelial to Mesenchymal Transition upon treatment with TGFß. Upon transformation, cells present nuclear invagination, the presence of micronuclei (white arrow), or donut-shaped nuclei. (C). Confocal image of TGFß-treated MCF10A cells highlight nuclear blebbing (red arrow) with a rupture in the Lamin B1 network. Cells are stained for Lamin B1 (LMNB1-green) and DNA (dapi-blue). Adapted from Comaills et al. [10].
Figure 4
Figure 4
Visualization and quantification of nuclear envelope disruption (NED). (A). Time lapse imaging of migrating MCF10A cells treated with TGFß and stably expressing the fluorescent markers YFP linked to the Nuclear Localization Signal (YFP-NLS) [74]. Confocal imaging in YFP channel and bright field allows the visualization of sudden leakage of YFP-NLs into the cytoplasm, showing a loss of proper compartmentalization of the nucleus during 8.30 mn and the loss of compartmentalization of the micronuclei at 12.10 mn of time. (B). Graph shows nuclear fluorescence intensity changes upon time in 10 cells with events of interphase NED/nuclear envelope repair observed in TGFß-treated MCF10A cells. Bold colored lines highlight repetitive NED events from the same cell. Adapted from Comaills et al. [10].
Figure 5
Figure 5
Nuclear envelope (NE) equilibrium and cases of nuclear envelope disruption (NED). (A). NE homeostasis between the chromatin rigidity forces (black arrow), cytoskeleton forces (green arrow), and the effect of the environment stiffness (blue arrow). Mechanosensitivity of the NE is done through the connection of the cytoskeleton by the LINC complex (blue ovals). (B). Example of nucleus with several NE abnormalities leading to extreme NE curvature at invagination, blebbing, or on the NE of the micronuclei that might be involved in NE fragility (highlighted in red). (C). Cells under migration have strong cytoskeleton attraction that can lead to local tension and the formation of nuclear envelope disruption. (D). Cells in migration through tiny constrictions also endure new stiffness forces and will deform NE locally to ensure the nuclear passage and create new NE tension and extreme NE bending, leading to NED. (E). Two daughter cells experiencing telomere fusion have their nucleus connected by a chromatin bridge and sharing the same NE. The need of extra NE to cover the extended NE surface leads to NE weakness and break.
Figure 6
Figure 6
The cGAS–cGAMP–STING signaling pathway: a universal sensor for double-strand DNA (dsDNA). (A). cGAS function is to sense DNA from the cytoplasm as result of infection, genomic, or mitochondrial instability. cGAS activation through the generation of cGAMP will drive the activation of the innate immune response and leads to the secretion of Interferon type 1 as well as a cocktail of cytokines. (B). Molecular mechanism of cGAS/STING pathway. cGAMP is the ligand for the STING receptor (shown in pink) and results in the activation of the transcription regulator factors NF-κβ and IRF-3 that drive the secretion of several pro-inflammatory molecules (Adapted from Ablasser et al. [100] and Motwani et al. [97]).
Figure 7
Figure 7
Chromosomal instability resulting from nuclear envelope disruption of micronuclei (MN). Defects in nuclear envelope of the micronuclei lead to it collapsing, resulting in defective replication and massive DNA damage. MN collapse is associated with a broad range of chromosomal rearrangements such as chromothripsis, the hyper mutated pattern kataegis, as well as the insertion, deletion, and translocation events. Circular chromosomes (ecDNA) are often associated with chromothripsis.
Figure 8
Figure 8
Chromosomal instability resulting from nuclear envelope disruption (NED) during telomere fusion. Dicentric chromosome under mitosis ends up in two daughter cells connected by a chromatin bridge. Studies have shown that the dicentric chromosome will break in response to NED and the attack of TREX1 proteins as well as due to extensive mechanical forces from the cytoskeleton. The resulting breaks will generate diverse structural variants as the formation of chromothripsis, kataegis as well as a located mutagenesis APOBEC signature. Furthermore, defective replication on the broken bridge of the chromosome scales up the genomic instability suffered by the cells that will progress in the formation of micronuclei in the next mitosis, increasing considerably the genomic instability (Adapted from Umbreit et al. [110] and Maciejowski et al. [70]).
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