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Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
The nucleus is bounded by the nuclear envelope, which encloses chromatin and the machinery necessary for gene transcription. The nucleus is a dynamic structure, which disassembles at the onset of mitosis and reassembles during telophase. The envelope consists of two membrane bilayers, posing a considerable hydrophobic barrier to macromolecular transport (Fig. 3). The outer nuclear membrane is continuous with the endoplasmic reticulum, and with the inner nuclear membrane forms a perinuclear space that is continuous with the endoplasmic reticulum lumen (82,83). The inner nuclear membrane is supported internally by the nuclear lamina, a network of lamin proteins that lines the inner side of the envelope (82). The lamina also is thought to provide attachment sites for chromatin (84-86). The very interior of the nucleus is a network of DNA, RNA, and proteins. It is the active transcriptions sites that are the targets of gene delivery.
Mitochondrial Stress and Cellular Senescence
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Irene L. Tan, Michael C. Velarde
Lamin B1 is a protein which comprises part of the nuclear lamina and helps in maintaining proper nuclear structure and function (Camps, Erdos, and Ried 2015). Senescent cells induced through MiDAS have lower expression of lamin B1 relative to dividing and undifferentiated cells (Wiley et al. 2016). Lamin B1 loss is also observed in RS and OIS (Freund et al. 2012). Cells induced to senesce by DNA-damaging agents, such as UV and X-ray irradiation, also exhibit decline in lamin B1 (Freund et al. 2012; Wang et al. 2017). Loss of lamin B1 in senescent cells is linked to the formation of SAHF (Sadaie et al. 2013) and nuclear blebs (Shimi et al. 2011).
Senescent Cells as Drivers of Age-Related Diseases
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Cielo Mae D. Marquez, Michael C. Velarde
The nuclear envelope is lined by the nuclear lamina, a dense fibrillary network which provides mechanical support and regulates size, shape, and stability of the nucleus [85,86]. Nuclear lamina also partakes in a number of other functions including regulation of DNA synthesis, RNA transcription, and chromatin organization [87]. In mammals, the lamina contains major structural proteins categorized as type A (lamin A and C) and type B (lamin B1 and B2) lamins based on their isoelectric points [85]. Nuclear lamins are dynamic structures that are assembled and disassembled throughout the cell cycle. Lamin A and C are derived from the gene LMNA by alternative splicing and are expressed by non-proliferating and differentiated cells. Lamin B1 and B2 are encoded by separate genes LMNB1 and LMNB2 respectively and are strongly expressed by dividing and undifferentiated cells [88–90]. While there are two types of lamin B, expression of one or the other is sufficient for cell survival [86,91]. Expression of type A and B lamins are differentially regulated in specific tissues during embryogenesis [91,92].
Ambient PM2.5 exposure causes cellular senescence via DNA damage, micronuclei formation, and cGAS activation
Published in Nanotoxicology, 2022
Tao Wu, Shengmin Xu, Biao Chen, Lingzhi Bao, Jie Ma, Wei Han, An Xu, Kwan Ngok Yu, Lijun Wu, Shaopeng Chen
It was puzzling that although cGAS accumulated on most MNs, there was no cGAS accumulation on a tiny minority of MNs following PM2.5 exposures. Research from a previous study demonstrated that NE rupture in primary nuclei was associated with disorganization in the nuclear lamina of cells (Hatch et al. 2013). According to the previous finding, those MNs gathered cGAS might have defects in the nuclear lamina assembly. To detect the integrity of lamina, we labeled cGAS and lamin A/C in fibroblasts exposed to PM2.5, and found that although cGAS gathered in most MNs with the discontinuous nuclear rim of lamin A/C, indicating disruption of MNs, a few MNs with the continuous nuclear rim of lamin A/C still accumulated cGAS. Further labeling of lamin B1 showed that almost every MN with discontinuous nuclear rim of lamin B1 gathered cGAS. Co-staining of laminB1 and lamin A/C showed that MNs with continuous nuclear rim of lamin A/C presented discontinuous nuclear rim of lamin B1. Statistical results showed that both lamin B1 (about 90%) and lamin A/C (about 40%) had different degrees of rupture, and the rate of lamin B1 disorganization was closely related to the rate of cGAS gathering (about 80%). Consistent with the localization of lamina, the protein levels of lamin B1 decreased significantly and lamin A/C did not downregulate that much. Thus, we demonstrated that disrupted MNs were a source of cGAS activation to aggravate cellular senescence and lamin B1 triggered MNs disruption upon PM2.5 exposures.
A review of protein-protein interaction and signaling pathway of Vimentin in cell regulation, morphology and cell differentiation in normal cells
Published in Journal of Receptors and Signal Transduction, 2022
Danial Hashemi Karoii, Hossein Azizi
The IFs that make up the nuclear lamina surrounding the inner nuclear membrane has been shown to influence gene transcription through protein-protein interactions and DNA replication [15,16]. On the other hand, Vimentin has been characterized as a possible transcriptional regulator since it can sequester transcriptional determinants and interact with them, such as p53 and menin, which collaborates with transcription factors AP1 and JunD [16,17]. Furthermore, Peter Traub and colleagues’ long-term research shows an altogether new aspect of Vimentin’s cellular and molecular activities. They have shown Vimentin’s capacity to interact with different specialized DNA structures, including, among other things, satellite DNA, telomere DNA retroposons, and mitochondrial DNA in a number of publications [18,19]. This connection between cytoplasmic Vimentin and genomic DNA is facilitated by VIF, which is found in nuclei and mitochondria. Wang and colleagues discovered that the N-terminal head of Vimentin is responsible for DNA binding. Recent studies have shown that Vimentin is related to mRNA for control stability, RNA binding, and double-stranded RNA binding [20–22].
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
HGPS is an ultra-rare genetic disease (prevalence 1 in 18 million people) characterized by accelerated aging and premature death at an average age of 14.6 years (www.progeriaresearch.org). Most HGPS patients are heterozygous carriers of a de novo synonymous mutation (c.1824C>T) in the LMNA gene [1,2], which encodes the nuclear lamina proteins lamin A and C, generated by alternative splicing. In normal cells, lamin A maturation includes the farnesylation, methylation, and subsequent cleavage of its C-terminus by the zinc metalloprotease ZMPSTE24. The HGPS mutation activates the use of a cryptic splice donor site in exon 11, generating an aberrant lamin A variant called progerin that lacks 50 amino acids spanning the ZMPSTE24 cleavage site and therefore remains permanently farnesylated and methylated [3] (Figure 1).