Spatiotemporal Mislocalization of Nuclear Membrane-Associated Proteins in γ-Irradiation-Induced Senescent Cells

Kovaříková, Alena Svobodová; Bártová, Eva; Kovařı́k, Aleš; Lukášová, Emı́lie

doi:10.3390/cells9040999

Cited by 4 publications

(2 citation statements)

References 44 publications

(74 reference statements)

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“…As cell cycle checkpoint pathways, the maintenance of the homeostasis between the nuclear envelope and telomeres may be tightly regulated and important for cell cycle progression. Interestingly, a recent study showed that the mislocalization of LINC complex proteins is a significant characteristic of cellular senescence [ 84 ]. Notably, RAP1 S205 phosphorylation, which is activated by p90RS activation, induces the nuclear export of the RAP1-TRF2 complex and further contributes to senescence and telomere dysfunction in epithelial cells [ 85 , 86 ].…”

Section: Discussionmentioning

confidence: 99%

Nuclear envelope tethering inhibits the formation of ALT-associated PML bodies in ALT cells

Yang

Hsieh

Sun

2021

Aging

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Telomere length homeostasis is essential for maintaining genomic stability and cancer proliferation. Telomerase-negative cancer cells undergo recombination-mediated alternative lengthening of telomeres. Telomeres associate with the nuclear envelope through the shelterin RAP1 and nuclear envelope SUN1 proteins. However, how the associations between telomeres and the nuclear envelope affect the progression of telomere recombination is not understood. Here, we show that telomere anchorage might inhibit telomere-telomere recombination. SUN1 depletion stimulates the formation of alternative lengthening of telomeres-associated promyelocytic leukemia bodies in ALT cells. In contrast, overexpression of a telomere-nuclear envelope-tethering chimera protein, RAP1-SUN1, suppresses APB formation. Moreover, inhibition of this nuclear envelope attachment alleviates the requirement of TOP3α for resolving the supercoiling pressure during telomere recombination. A coimmunoprecipitation assay revealed that the SUN1 N-terminal nucleoplasmic domain interacts with the RAP1 middle coil domain, and phosphorylation-mimetic mutations in RAP1 inhibit this interaction. However, abolishing the RAP1-SUN1 interaction does not hinder APB formation, which hints at the existence of another SUN1-dependent telomere anchorage pathway. In summary, our results reveal an inhibitory role of telomere-nuclear envelope association in telomere-telomere recombination and imply the presence of redundant pathways for the telomere-nuclear envelope association in ALT cells.

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Section: Discussionmentioning

confidence: 99%

Nuclear envelope tethering inhibits the formation of ALT-associated PML bodies in ALT cells

Yang

Hsieh

Sun

2021

Aging

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“…The distribution pattern of nuclear envelope (NE) protein is an important prerequisite for its biological functions [30][31][32] . To this end, we first investigated how actomyosin contractility affects the distribution of SUN2 on the nuclear membrane.…”

Section: Actomyosin Contractility Level Regulates the Ratio Of Sun2 D...mentioning

confidence: 99%

Perinuclear force regulates SUN2 dynamics and distribution on the nuclear envelope for proper nuclear mechanotransduction

Niu

Wang

Zhao

et al. 2022

Preprint

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The trans-luminal LINC (Linker of Nucleoskeleton and Cytoskeleton) complex plays a central role in nuclear mechanotransduction by coupling the nucleus with cytoskeleton. High spatial density and active dynamics of LINC complex have hindered its precise characterization for the understanding of underlying mechanisms how the linkages sense and respond to mechanical stimuli. In this study, we focus on SUN2, a core component of LINC complex interconnecting the nuclear lamina and actin cytoskeleton and apply single molecule super-resolution imaging to reveal how SUN2 responds to actomyosin contractility. Using stochastic optical reconstruction microscopy (STORM), we quantitated the distribution pattern and density of SUN2 on the basal nuclear membrane. We found that SUN2 undergoes bidirectional translocation between ER and nuclear membrane in response to actomyosin contractility, suggesting that dynamic constrained force on SUN2 is required for its proper distribution. Furthermore, single molecule imaging unveils interesting dynamics of SUN2 molecules that are regulated by both actomyosin contractility and laminA/C network, whereas SUN2 oligomeric states are not affected by actomyosin contractility. Lastly, the mechanical response of SUN2 to actomyosin contractility was found to regulate expression of mechano-sensitive genes located in lamina-associated domains (LADs) and perinuclear heterochromatin. Taken together, our results reveal how SUN2 responds to mechanical cues at the single-molecule level, providing new insights into the mechanism of nuclear mechanotransduction.

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From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

et al. 2021

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Among oral tissues, the periodontium is permanently subjected to mechanical forces resulting from chewing, mastication, or orthodontic appliances. Molecularly, these movements induce a series of subsequent signaling processes, which are embedded in the biological concept of cellular mechanotransduction (MT). Cell and tissue structures, ranging from the extracellular matrix (ECM) to the plasma membrane, the cytosol and the nucleus, are involved in MT. Dysregulation of the diverse, fine-tuned interaction of molecular players responsible for transmitting biophysical environmental information into the cell’s inner milieu can lead to and promote serious diseases, such as periodontitis or oral squamous cell carcinoma (OSCC). Therefore, periodontal integrity and regeneration is highly dependent on the proper integration and regulation of mechanobiological signals in the context of cell behavior. Recent experimental findings have increased the understanding of classical cellular mechanosensing mechanisms by both integrating exogenic factors such as bacterial gingipain proteases and newly discovered cell-inherent functions of mechanoresponsive co-transcriptional regulators such as the Yes-associated protein 1 (YAP1) or the nuclear cytoskeleton. Regarding periodontal MT research, this review offers insights into the current trends and open aspects. Concerning oral regenerative medicine or weakening of periodontal tissue diseases, perspectives on future applications of mechanobiological principles are discussed.

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Spatiotemporal Mislocalization of Nuclear Membrane-Associated Proteins in γ-Irradiation-Induced Senescent Cells

Cited by 4 publications

References 44 publications

Nuclear envelope tethering inhibits the formation of ALT-associated PML bodies in ALT cells

Nuclear envelope tethering inhibits the formation of ALT-associated PML bodies in ALT cells

Perinuclear force regulates SUN2 dynamics and distribution on the nuclear envelope for proper nuclear mechanotransduction

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

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