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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Mitotic errors in chromosome segregation lead to mosaic embryos. The incidence of mosaicism in human embryos is currently being debated (64,113), but in contrast to our growing knowledge of basic biological mechanisms that lead to aneuploidy in human oocytes, analysis of cell divisions and chromosome segregation errors in preimplantation embryos is less developed. Many models are inferred from knowledge obtained in mitosis in cell lines (e.g., reviewed by [114]). However, ethical regulations and the technical challenges of linage tracing and single-cell genomics limit our ability for direct observations in embryos. In particular, classical loss-of-function and gain-of-function analyses that are used to infer gene function are challenging in embryos. This area of research will likely evolve rapidly in the coming years since ethical permission has been granted in several countries to use CRISPR-Cas9 for gene editing. Despite the limitations, major insights into chromosomal aneuploidy in embryos have been obtained from the use of preimplantation genetic screening and diagnosis (PGD/PGS) to prevent aneuploid conceptions and the inheritance of monogenic diseases.
Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Aurora kinases have recently gained prominence as potential anticancer drug targets. Most research has focused on Aurora A and B as they appear to play a role in oncogenesis, with Aurora A identified as a low-penetrance tumor susceptibility gene in mice and humans. All three kinases localize to the centrosome during the different phases of mitosis and regulate cell-cycle transit from G2 through cytokinesis. Dysfunction of these kinases in cells has been associated with defects in chromosome segregation which can cause genetic instability, a condition highly correlated with tumorigenesis. Thus, Aurora A is frequently found to be amplified in a variety of tumor types and displays oncogenic activity. Aurora B is a positive regulator of mitosis that facilitates attachment of the mitotic spindle to the centromere, the segregation of sister chromatids to each daughter cell, and the separation of daughter cells during cytokinesis. It may be amplified and overexpressed by a variety of cancer cell types. Therefore, there is growing evidence that inhibition of these kinases may have therapeutic potential in cancer due to their important roles in the cell division process.
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
Chromosomes are guided through the cytoplasm by connection of microtubules emanating from the microtubule organizing center (MTOC) and terminating on the kinetochore attachment on the chromosome. This attachment ensures proper chromosome segregation during mitosis and close proximity of chromosomes during reformation of the nuclear envelope. Plasmid DNA lacks the kinetochore protein attachment site for microtubules, so it is unlikely that microtubules would associate with plasmid DNA and assist in the colocalization of plasmid with host DNA. Therefore, random events would be required to colocalize plasmid and genomic DNA during nuclear envelope reformation.
Targeting TANK-binding kinase 1 (TBK1) in cancer
Published in Expert Opinion on Therapeutic Targets, 2020
Or-Yam Revach, Shuming Liu, Russell W. Jenkins
TBK1 is induced at mitosis and directly phosphorylates the mitotic kinase, Polo-like kinase 1 (PLK1) and its upstream regulator AKT [42]. In line with that, TBK1 activating phosphorylation on pSer172, was increased during mitosis, and loss of TBK1 blocked mitotic-associated phosphorylation of PLK1. Other substrates of mitosis including CEP170 and NUMA, that colocalize with TBK1 in centrosomes [95]. TBK1 is necessary for CEP170 centrosomal localization and binding to the microtubule depolymerase Kif2b, as well as, for NUMA binding to the microtubule motor dynein. Inhibition of TBK1 binding to CEP170 results in microtubule instability and defects in mitosis. Optineurin and the PINK1/Parkin pathway regulate mitophagy via TBK1 in a cell-cycle dependent manner [88,96], providing an intriguing connection between autophagy/mitophagy, the cell cycle, and innate immune signaling. This biology may have implications for cancer cell growth, as recruitment of TBK1 to the mitochondria (by PINK1/Parkin) results in a G2/M block due to loss of TBK1 at centrosomes and mitotic spindles. In A549 cancer cells, inhibition of TBK1 led to an increase in tetraploid cells indicating a role for TBK1 in mitotic progression [95] and suggesting that impaired TBK1 signaling in cancer cells may impact successful chromosome segregation. The impact of TBK1 deletion or inhibition on accumulated chromosomal alterations, both acutely and over time, as well as the upstream signals promoting TBK1 activation before entering mitosis, remain unclear and will require further investigation.
Zoledronic acid induces cytogenetic toxicity in male germline cells of Swiss albino mice
Published in Drug and Chemical Toxicology, 2019
Ramakrishna Dasari, Sunil Misra
Aberrant chromosomal segregation is a consequence of errors in the series of programed and sequential events occurring at prophase-I of meiosis defined by a number of characteristic morphological changes associated with the pairing of homologous chromosomes, synapsis, asynapsis, and recombination (Garcia-Muse and Boulton 2007). For analyzing the cytogenetic toxicity of ZA, three different concentrations (2, 4, and 8 mg/kg b.wt.) were exposed to mice. The group of positive control mice that received CP induced significantly higher percentage of CAs in the spermatogonial cells which are in agreement with the earlier reports (Rathenberg 1975, Choudhury et al. 2002). Further, CP induced a significantly higher percentage of aberrant primary spermatocytes with atypical bivalents at week 4 posttreatment and also significantly higher percentage of abnormal sperms at week 8 posttreatment justifying its clastogenic potential in germline cells.
Evaluation of the impact of sperm morphology on embryo aneuploidy rates in a donor oocyte program
Published in Systems Biology in Reproductive Medicine, 2018
Onder Coban, Munevver Serdarogullari, Zehra Onar Sekerci, Ekrem Murat Bilgin, Nedime Serakinci
Although the present study utilized donor oocytes to minimize the impact of age related maternal contribution to the incidence of embryo aneuploidy, which has been found to be high in earlier studies (Martini et al. 1998), the precise inference about source of aneuploidy could be complicated. The contribution of other factors, like meiotic chromosomal rearrangements and embryo mosaicism depending on abnormal chromosomal segregation during cell division (mitosis), need to be assessed in order to support these findings. Furthermore, factors such as gamete production, fertilization, embryonic development, age, and many others should be considered during the investigation of the source of numerical chromosome abnormalities in preimplantation embryos. At this juncture our results suggested that sperm low quality/morphology is associated with the incidence of embryo aneuploidy.