Chromosome nondisjunction during bipolar mitoses of binucleated intermediates promote aneuploidy formation along with multipolar mitoses rather than chromosome loss in micronuclei induced by asbestos

Zhang, Tianwei; Lv, Lei; Huang, Yun; Ren, Xiaohui; Shi, Qinghua

doi:10.18632/oncotarget.14212

Cited by 11 publications

(5 citation statements)

References 44 publications

(63 reference statements)

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“…Asbestos-induced chromosomal instability and consequent aneuploidy, a hallmark of cancer cells, has been observed in various types of in vitro cultured mammalian cells [32–39]. Recently, Zhang et al [40] has demonstrated that aneuploid cells are generated from binucleated cells through multipolar mitosis or bipolar mitosis with chromosome nondisjunction. Changes in the copy numbers of chromosomes or large chromosomal regions in aneuploid cells significantly alter the expression of several hundreds of genes.…”

Section: Resultsmentioning

confidence: 99%

Live-cell imaging of macrophage phagocytosis of asbestos fibers under fluorescence microscopy

et al. 2019

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Background Frustrated phagocytosis occurs when an asbestos fiber > 10 μm in length is engulfed imperfectly by a macrophage, and it is believed to be associated with chromosomal instability. Few studies have focused on dynamic cellular imaging to assess the toxicity of hazardous inorganic materials such as asbestos. One reason for this is the relative lack of fluorescent probes available to facilitate experimental visualization of inorganic materials. We recently developed asbestos-specific fluorescent probes based on asbestos-binding proteins, and achieved efficient fluorescent labeling of asbestos. Results Live-cell imaging with fluorescent asbestos probes was successfully utilized to dynamically analyze asbestos phagocytosis. The fluorescently labeled asbestos fibers were phagocytosed by RAW 264.7 macrophages. Internalized fibers of < 5 μm in length were visualized clearly via overlaid phase contrast and fluorescence microscopy images, but they were not clearly depicted using phase contrast images alone. Approximately 60% of the cells had phagocytosed asbestos fibers after 2 h, but over 96% of cells remained alive even 24 h after the addition of asbestos fibers. Immediate cell death was only observed when an asbestos fiber was physically pulled from a cell by an external force. Notably, at 24 h after the addition of asbestos fibers an approximately 4-fold increase in the number of binucleated cells was observed. Monitoring of individual cell divisions of cells that had phagocytosed asbestos suggested that binucleated cells were formed via the inhibition of cell separation, by asbestos fibers of > 10 μm in length that were localized in the proximity of the intercellular bridge. Conclusions Fluorescently labeled asbestos facilitated visualization of the dynamic biological processes that occur during and after the internalization of asbestos fibers, and indicated that (i) frustrated phagocytosis itself does not lead to immediate cell death unless the asbestos fiber is physically pulled from the cell by an external force, and (ii) macrophages that have phagocytosed asbestos can divide but sometimes the resulting daughter cells fuse, leading to the formation of a binucleated cell. This fusion only seemed to occur when a comparatively long asbestos fiber (> 10 μm) was shared by two daughter cells. Electronic supplementary material The online version of this article (10.1186/s41021-019-0129-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Live-cell imaging of macrophage phagocytosis of asbestos fibers under fluorescence microscopy

et al. 2019

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“…Since inactivation of the proteasome by RNAi or use of inhibitors produces aberrant nuclei in C. elegans germline [ 43 , 50 ] and BAP1 has a regulatory function on ubiquitination of histones [ 55 ], genome instability would be the “hallmark of cancer” behind the BAP1 alterations. Interestingly, although the specific mechanism of carcinogenesis induced by asbestos in MPM is still unclear, it has been proposed that asbestos causes genome instability [ 56 ] and chromosomal segregation defects [ 57 ]. Given the limited effective therapeutic intervention in MPM [ 58 ], and that about 50% of cases of MPM present alteration in BAP1 [ 59 ], the development of animal models such as the one presented here would open new venues to detect vulnerabilities of cells with mutations in BAP1 .…”

Section: Discussionmentioning

confidence: 99%

BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13

Martínez-Fernández

Jha

Aliagas

et al. 2023

Cells

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The deubiquitinase BAP1 (BRCA1-associated protein 1) is associated with BAP1 tumor predisposition syndrome (TPDS). BAP1 is a tumor suppressor gene whose alterations in cancer are commonly caused by gene mutations leading to protein loss of function. By CRISPR-Cas, we have generated mutations in ubh-4, the BAP1 ortholog in Caenorhabditis elegans, to model the functional impact of BAP1 mutations. We have found that a mimicked BAP1 cancer missense mutation (UBH-4 A87D; BAP1 A95D) resembles the phenotypes of ubh-4 deletion mutants. Despite ubh-4 being ubiquitously expressed, the gene is not essential for viability and its deletion causes only mild phenotypes without affecting 20S proteasome levels. Such viability facilitated an RNAi screen for ubh-4 genetic interactors that identified rpn-9, the ortholog of human PSMD13, a gene encoding subunit of the regulatory particle of the 26S proteasome. ubh-4[A87D], similarly to ubh-4 deletion, cause a synthetic genetic interaction with rpn-9 inactivation affecting body size, lifespan, and the development of germ cells. Finally, we show how ubh-4 inactivation sensitizes animals to the chemotherapeutic agent Bortezomib, which is a proteasome inhibitor. Thus, we have established a model to study BAP1 cancer-related mutations in C. elegans, and our data points toward vulnerabilities that should be studied to explore therapeutic opportunities within the complexity of BAP1 tumors.

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“…In addition to all the other above-mentioned metabolic readjustments that TNT-linked cells may have to deal with, the intrusion and influx of cytoplasmic material from a non-dividing cell could definitely affect the entire geometry of a mitotic cell with its otherwise orderly aligned chromosomes and its highly vulnerable intricate spindle scaffold (Ong and Torres, 2020). Depending on the site of the TNTs intrusion relative to the cell equator and depending on the magnitude of its exerted effect, such an interference could displace and move the metaphase plate with its accurately arranged chromatids and, consequently, also reposition the cell's division plane and cytokinetic cleavage furrow in an analogous but much more subtle fashion as, for instance, was shown for asbestos fibers (Zhang et al, 2017;Ong and Torres, 2020). Together with the possible direct disruption of spindle tubules, such developments could ultimately lead to a maldistribution and irregular segregation of chromosomes into daughter cells, which are only able to survive and prosper in case they receive a proper fitting set of compatible chromosomes (Figure 4).…”

Section: Tunneling Nanotubesmentioning

confidence: 92%

Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges

Haas

2021

Front. Cell Dev. Biol.

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Stable aneuploid genomes with nonrandom numerical changes in uneven ploidy ranges define distinct subsets of hematologic malignancies and solid tumors. The idea put forward herein suggests that they emerge from interactions between diploid mitotic and G0/G1 cells, which can in a single step produce all combinations of mono-, di-, tri-, tetra- and pentasomic paternal/maternal homologue configurations that define such genomes. A nanotube-mediated influx of interphase cell cytoplasm into mitotic cells would thus be responsible for the critical nondisjunction and segregation errors by physically impeding the proper formation of the cell division machinery, whereas only a complete cell fusion can simultaneously generate pentasomies, uniparental trisomies as well as biclonal hypo- and hyperdiploid cell populations. The term “somatic sex” was devised to accentuate the similarities between germ cell and somatic cell fusions. A somatic cell fusion, in particular, recapitulates many processes that are also instrumental in the formation of an abnormal zygote that involves a diploid oocyte and a haploid sperm, which then may further develop into a digynic triploid embryo. Despite their somehow deceptive differences and consequences, the resemblance of these two routes may go far beyond of what has hitherto been appreciated. Based on the arguments put forward herein, I propose that embryonic malignancies of mesenchymal origin with these particular types of aneuploidies can thus be viewed as the kind of flawed somatic equivalent of a digynic triploid embryo.

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Chromosome nondisjunction during bipolar mitoses of binucleated intermediates promote aneuploidy formation along with multipolar mitoses rather than chromosome loss in micronuclei induced by asbestos

Cited by 11 publications

References 44 publications

Live-cell imaging of macrophage phagocytosis of asbestos fibers under fluorescence microscopy

Live-cell imaging of macrophage phagocytosis of asbestos fibers under fluorescence microscopy

BAP1 Malignant Pleural Mesothelioma Mutations in Caenorhabditis elegans Reveal Synthetic Lethality between ubh-4/BAP1 and the Proteasome Subunit rpn-9/PSMD13

Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges

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