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

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.

Investigations concerning the impact of consumption of hot beverages on acute cytotoxic and genotoxic effects in oral mucosa cells

“…However, it cannot be excluded that genetic damage occurred at later stages of cancer development. It is known that hot drinks cause esophagitis and dysplasia which represent premalignant lesions 28 , and it is well documented that inflammations are associated with an increase of chromosomal aberrations that lead to formation of MN 46 .…”

Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

“…Nuclear squeezing [ 46 , 47 ] and extensive forces during migration [ 34 ] can lead to transient NER. Noteworthy, nuclear envelope fragility and NER are also associated to other events [ 27 ] such as viral infection [ 86 , 87 , 88 , 89 ], some neuropathies [ 90 ], aging [ 91 ] or as a consequence of impairment in lamin levels [ 91 , 92 , 93 ] or function as in some type of laminopathy [ 94 ]. Over the past 10 years, the research on NE biology has revealed unexpected consequences of its deregulation and has shown the implication of NER in unexpected diseases such as in cancer.…”

“…The nucleus is compartmentalized from the cytoplasm by the Nuclear Envelope (NE), a lipid bilayer reinforced on its inner side by the nuclear lamina, a sheet-like structure of diverse proteins such as Lamin A and B as well as other components (For a review see [ 27 ]). The nucleus is generally rounded and stiffer than the cytoplasm [ 28 ], and thus can be the rate limiting step to the constriction imposed by cell migration.…”

“…During the migration and passage through constrictions, the cytoskeleton imposes considerable traction forces, resulting in extreme nuclear deformation ( Figure 2 C,D) that can surpass the adaptation capacity of the NE. The resulting shape distortion can lead to NE blebbing and extreme curvation causing the collapse of the NE during the interphase [ 27 ]. The use of time-lapse imaging [ 34 , 46 , 47 ] has allowed the observation and quantification of the NE collapse, also called Nuclear Envelope Rupture (NER).…”

“…Importantly, all these complex and simple chromosomic events are known to originate from the NER of micronuclei [ 55 , 56 , 57 , 58 ] or during the NER of cells presenting a chromatin bridge during a telomere crisis [ 59 , 60 , 61 ] ( Figure 3 ). Micronuclei are small nuclei found next to the main nucleus in cancer cells that contain a full chromosome or a chromosome fragment, and are the result of aberrant mitosis [ 27 ]. It is noteworthy that the NE of these micronuclei is fragile and tends to disrupt without the possibility of proper repair [ 48 , 49 ].…”