In vitro functional analysis has demonstrated that hyperactivation of ESCRT III results in the loss of integrity of the NE. ĭespite the crucial roles of these factors in repairing ruptured NE, dysregulation of their activities potentially disrupts the integrity of the NE. It has been proposed that LEM domain proteins further recruit endosomal sorting complex required for transport III (ESCRT III), which mediates the resealing of ruptured NE. Indeed, several factors involved in repairing ruptured NE have been identified, including a small DNA binding protein, Barrier-to-autointegration factor (BAF), and its binding partners, Lap2-emerin-MAN1 (LEM) domain proteins, which integrate into the inner nuclear membrane. Time-lapse imaging has revealed that most NE rupture is repaired within an hour, indicating the presence of machinery to carry out such repair. Mechanistically, studies have suggested that the mislocalization of cytoplasmic DNase and/or nuclear DNA repair factors is responsible for such DNA damage. Regarding the pathology of cancer, NE rupture has been proposed to trigger genome instability and increased cellular invasion through DNA damage. Accumulating evidence has revealed that NE rupture is involved in a broad spectrum of diseases ranging from cancer to neurodegenerative diseases. This can include both physiological and pathological events such as the radial migration of neural progenitors during brain development and the invasion of tumor cells into surrounding tissues, respectively. Cell migration through confined environments is one of the major causes of NE rupture. Mechanical NE stress frequently results in the rupture of the NE. Such stresses are referred to as “NE stress”. Previous studies demonstrated that the NE is damaged upon various types of stresses, leading to its dysfunction. The nuclear envelope (NE) encloses genomic DNA to protect it from a variety of insults and plays pivotal roles in regulating genomic function. These findings imply that dysregulation of cell cycle progression in cancer cells causes loss of the NE integrity and its consequences such as DNA damage and cell death upon mechanical NE stress. Furthermore, attenuation of cell cycle progression by inducing p21 in U251MG counteracted the nuclear deformation and DNA damage upon NE stress. Indeed, visualization of cell cycle stages using fluorescent ubiquitination-based cell cycle indicator reporters revealed greater resistance of U251MG to NE stress at G 1 phase than at S and G 2 phases. U251MG proliferated more rapidly than U87MG concomitant with reduced expression of p21, a major inhibitor of cyclin-dependent kinases, suggesting a correlation between NE stress response and cell cycle progression. These differences were unlikely to have been due to weakened NE in U251MG because the expression levels of lamin A/C, determinants of the physical property of the NE, were comparable and loss of compartmentalization across the NE was observed just after laser ablation of the NE in both cell lines. Time-lapse imaging demonstrated that repairing of ruptured NE often failed in U251MG, but not in U87MG. In contrast, another cell line derived from glioblastoma, U87MG, only presented mild nuclear deformation without DNA damage. U251MG derived from glioblastoma exhibited severe nuclear deformation and massive DNA damage at the deformed nuclear region upon mechanical NE stress. Here, we showed that response to NE stress varied among different types of cancer cell lines. Although several proteins involved in the reassembly of the NE after mitosis have been identified as the NE repair factors, the regulatory mechanisms modulating the efficiency of NE repair remain unclear. Accumulating evidence has proven the pathological relevance of NE stress in numerous diseases ranging from cancer to neurodegenerative diseases. The nuclear envelope (NE) is often challenged by various stresses (known as “NE stress”), leading to its dysfunction.
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