Figure 8.

Model for the formation of micronuclei. Models for DM elimination by budding and micronucleation in S-phase and postmitotic micronucleation are shown. In the S-phase budding mechanism, DMs are preferentially located at the periphery of the interphase nucleus and then selectively encapsulated into nuclear buds that then pinch off to form micronuclei during DNA replication (a–d). This process is an alternative to the classical postmitotic mechanism of generating micronuclei depicted in f–h. One possible fate of these micronuclei is that they refuse to the main nucleus (i to j and d to e). At present, this is a speculation as there is no direct experimental evidence to support it. On the other hand, we do have direct evidence that micronuclei can be released into the culture supernatant as extracellular micronuclei, suggesting that they may be extruded through the cell membrane (j; Shimizu, N., and G.M. Wahl, unpublished data). Decrease in DM content can be achieved by either expulsion of micronuclei containing DMs from the cell, or by degradation of DM–DNA within intracellular micronuclei. In either case, loss of DM sequences from the nucleus results in reversion of the tumor phenotype, differentiation, or apoptosis (k; Von Hoff et al., 1992; Eckhardt et al., 1994; Shimizu et al., 1994).