Aneuploidy in Human Oocytes and Preimplantation Embryos
Carlos Simón, Carmen Rubio in 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.
Genetic Susceptibility to Colorectal Cancer
Jim Cassidy, Patrick Johnston, Eric Van Cutsem in Colorectal Cancer, 2006
APC also plays a key role in the microtubule cytoskeleton, binding to microtubules as well as promoting their formation and presenting them to the kinetochore (105–106). The organization and structure of microtubules is vital to cell division and migration, and truncated forms of the APC protein appear to be unable to bind microtubules (107). Not only does APC bind microtubules but is also involved in mediating attachment of chromosomes to the spindle apparatus in order to accurately separate the sister chromatids during mitosis. Mouse cells homozygous for a truncating mutation, Apcmin~, displayed abnormal chromosome patterns when compared with wildtype counterparts (105). This suggests that APC plays an important role in maintaining fidelity of chromosome segregation and thereby control of chromosome number. This is supported by the observation that aneuploidy occurs in the majority of colorectal cancers with APC mutations and underscores the complexity of the role that APC mutations play, suppressing tumorigenesis and progression. The carboxy terminus of the APC protein not only binds microtubules but also the microtubule binding protein EB1 (108) and the tumor suppressor protein Dlg (109), both of which are implicated in tumorigenesis.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow in Fetal and Perinatal Skeletal Dysplasias, 2012
Genetics: autosomal recessive disorder caused by mutations in the gene ESCO2 (establishment of cohesion 1 homolog 2), encoding an acetyltransferase required for the establishment of sister chromatid cohesion during the S phase of the cell cycle. Cohesion of sister chromatids is essential for correct chromosome segregation and genomic stability. Cells of patients affected by RBS show a phenomenon known as premature centromere separation (PCS) or heterochromatin repulsion (HR), which manifests itself as absence of the centromeric constriction and ‘puffing’ at the heterochromatic regions. This phenomenon can cause random chromosome loss and micronuclei and/or nuclear lobulation in the interphase cells. RBS cells also exhibit hypersensitivity to clastogens such as mitomycin C (MMC), cisplatin and gamma and UV radiation. Because of the cohesion defect, there is an increase in cell death and a decreased proliferation capacity, which is at the root of the reduced growth and developmental phenotype in RBS.
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.
An overview of potential novel mechanisms of action underlying Tumor Treating Fields-induced cancer cell death and their clinical implications
Published in International Journal of Radiation Biology, 2021
Narasimha Kumar Karanam, Michael D. Story
Anti-mitotic agents are highly selective and effective because the loss of cell cycle control is a hallmark of cancer. Mitosis is a complex and elaborate process, but it is also the shortest and most fragile phase of the cell cycle. The whole cell cycle is tightly regulated through several checkpoints to ensure elimination of mitotically defective and severely damaged cells by triggering mitotic catastrophe and apoptotic cell death or senescence processes. Several studies have reported that TTFields exposure results in the accumulation of cells in the G2/M phase of the cell cycle, suggesting that the G2/M checkpoint may be triggered to prevent cells from prematurely entering mitosis. The major cell cycle control mechanism in mitosis is the spindle assembly checkpoint (SAC), which will induce prolonged mitotic arrest to assure that accurate chromosomal segregation takes place. Giladi, Schneiderman, et al. (2015) observed such prolonged mitotic arrest in cells exposed to TTFields and Kessler et al. (2018) recently showed that TTFields increase the efficacy of the SAC check point inhibitor MPS1-IN-3 in GBM cells.