Chromosomes missegregated into micronuclei contribute to chromosomal instability by missegregating at the next division

Abstract

Micronuclei (MNi) are extranuclear DNA-containing structures that form upon mitotic exit from unsegregated chromosome fragments or anaphase lagging (whole) chromosomes (LCs). MNi formed from whole chromosomes are of particular interest because LCs are observed in both cancer and non-cancer cells, and are recognized as a major source of chromosomal instability (CIN) in cancer cells. Here, we generated a PtK1 cell line expressing a photoactivatable H2B histone to study the behavior of whole chromosome-containing MNi at the mitosis following their formation. Importantly, MNi of PtK1 cells did not display the membrane rupture or transport defects reported for other cell types. Despite this, we found that most micronucleated cells displayed some kind of chromosome segregation defect and that the missegregating chromosome was the one derived from the MN. Moreover, condensation of the chromosome within the MN was frequently delayed and associated with failure to align at the metaphase plate. Finally, the defective condensation of the MN-derived chromosomes could also explain the frequent occurrence of cytokinesis failure in micronucleated cells. In summary, we find that chromosomes from MNi may trigger a CIN phenotype by missegregating at the mitosis following MN formation.

Chromosome instability induced by a single defined sister chromatid fusion

“…We noticed that these subtypes of acentric X chromosomes are often more massive than the parental X chromosome, and possess reduced FISH signal compared with the parental X chromosome (Fig 3B and D). Such characteristics suggest that these acentric X chromosomes failed in mitotic condensation and support the notion that they derived from MN (He et al, 2019). Therefore, we propose that even a single SCF can generate MN and acentric chromosome fragments, which is followed by cell cycle destabilization.…”

Mutations in <i>mxc</i> Tumor-Suppressor Gene Induce Chromosome Instability in <i>Drosophila</i> Male Meiosis

“…There are some reports of chromosome aneuploidy contributing to tumorigenesis (Gisselsson, 2008;Holland and Cleveland, 2009). As a recent study also demonstrated, once micronuclei are produced from unsegregated chromosome fragments or whole chromosomes, they contribute to CIN at the next cell division (He et al, 2019). Considering these results, we hypothesize that a subtle aberration in chromosome construction can induce CIN in cooperation with the perturbation of M-phase-checkpoint regulation.…”

Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy

“…It is well known that DNA damage and chromosomal structural aberrations, such as translocations, are closely related to chromosome missegregation during mitosis [93]; such aberrations could be the result of extra centrosomes and merotelic-kinetochore-microtubule attachment errors, which can occur in polyploid cells [94][95][96][97][98]. Extra centrosomes in cells can originate by several mechanisms, including centrosome overduplication, de novo synthesis of centrosomes, mitotic slippage, cytokinesis defects, and cell fusion (for review see [91,92,99]).…”

“…As a consequence, DNA replication is impaired and aberrant in micronuclei, which results in DNA intermediates rather than in intact chromosomes [101,102] Moreover, micronucleic DNA structures are additionally prone to DNA double strand breaks due to the influx of cytosolic nucleases [101][102][103]. Recently, He and colleagues demonstrated that micronuclei-derived DNA intermediates and fragments are missegregated again at the subsequent round of mitosis, thereby triggering the cells' overall genomic instability [94]. Moreover, micronuclei-derived DNA fragments inside the newly formed daughter cell nucleus could be reassembled through error-prone nonhomologous end joining due to activation of DNA damage repair mechanisms [103][104][105][106].…”