CHAPTER 2: Mechanisms by Which Genotoxins Cause Micronuclei and Other Nuclear Anomalies
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Published:18 Jul 2019
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Special Collection: 2019 ebook collectionSeries: Issues in Toxicology
M. Fenech, in The Micronucleus Assay in Toxicology, ed. S. Knasmüller and M. Fenech, The Royal Society of Chemistry, 2019, pp. 8-23.
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Normal eukaryotic cells contain a single nucleus. However, abnormal small nuclei known as micronuclei, additional to the main nucleus, may occur in cells that are exposed to genotoxic agents (chemicals and/or radiation) that cause structural or numerical chromosome aberrations. Micronuclei originate from chromosome fragments or whole chromosomes that lag behind during anaphase in mitosis. This occurs because most chromosome fragments lack centromeres or because some of the whole chromosomes have defective centromeres and/or kinetochores, which results in their inability to engage with the mitotic spindle. An alternative mechanism for these events is malfunction of the mitotic spindle. The molecular mechanisms that cause chromosome fragmentation can also result in the formation of asymmetrical chromosome rearrangements such as dicentric chromosomes. The centromeres of dicentric chromosomes are often pulled in opposite directions during anaphase leading to the formation of anaphase bridges that can be observed as nucleoplasmic bridges during the binucleated stage in telophase. The formation of nucleoplasmic bridges leads to hypermutation via breakage–fusion–bridge cycles causing gene amplification and ultimately to the extrusion of the amplified DNA via nuclear budding. Using the cytokinesis-block technique it is possible to identify micronuclei, nucleoplasmic bridges and nuclear buds simultaneously because the cells are halted at the binucleated stage in mitosis, which is the ideal stage to observe and measured these nuclear anomalies. Recent studies have also shown that entrapment of a chromosome within a micronucleus may result in the shattering of the chromosome (chromothripsis) followed by random rearrangement and ligation of the fragments leading to the formation of an abnormal chromosome (chromoanagenesis). Thus, formation of micronuclei and nucleoplasmic bridges are themselves events that generate further chromosomal instability.