Abstract
Mitotic death is a delayed response of p53 mutant tumours that are resistant to genotoxic damage. Questions surround why this response is so delayed and how its mechanisms serve a survival function. After uncoupling apoptosis from G1 and S phase arrests and adapting these checkpoints, p53 mutated tumour cells arrive at the G2 compartment where decisions regarding survival and death are made. Missed or insufficient DNA repair in G1 and S phases after severe genotoxic damage results in cells arriving in G2 with an accumulation of point mutations and chromosome breaks. Double strand breaks can be repaired by homologous recombination during G2 arrest. However, cells with excessive chromosome lesions either directly bypass the G2/M checkpoint, starting endocycles from G2 arrest, or are subsequently detected by the spindle checkpoint and present with the features of mitotic death. These complex features include apoptosis from metaphase and mitosis restitution, the latter of which can also facilitate transient endocycles, producing endopolyploid cells. The ability of cells to initiate endocycles during G2 arrest and mitosis restitution most likely reflects their similar molecular environments, with down-regulated mitosis promoting factor activity. Resulting endocycling cells have the ability to repair damaged DNA, and although mostly reproductively dead, in some cases give rise to mitotic progeny. We conclude that the features of mitotic death do not simply represent aberrations of dying cells but are indicative of a switch to amitotic modes of cell survival that may provide additional mechanisms of genotoxic resistance.
Highlights
Following severe genotoxic damage, cells undergo either rapid or delayed death termed by Okada [1] as interphase and reproductive deaths, respectively
The main features of mitotic death have been described by several workers [6,7,8]
They include (a) the absence/delay of the G1/S checkpoint and (b) the absence of interphase apoptosis coupled to this checkpoint; (c) delay in the G2 compartment followed by its adaptation and (d) a sequence of aberrant mitoses which end in mitotic death; (e) formation and disintegration of giant cells
Summary
Cells undergo either rapid or delayed death termed by Okada [1] as interphase and reproductive deaths, respectively. In hyperploid cells, sister chromatids usually do not become separated after replication rounds [44,46,48] and especially if slightly condensed, retain partial cohesion at highly reiterated sites Most likely, such a polytenic kind of endopolyploidy arises initially from cells arrested in the G2/M or spindle checkpoint and renders these nuclei unable to segregate chromosomes by mitosis. For recombination and somatic reduction to happen, reorganisation of endopolyploid nuclei should occur to provide pairing of homologous chromosomes In support of this suggestion, a complex somatic reduction process involving meioticlike bouquets has been reported recently by our group for some Burkitt's lymphoma cell lines after high doses of irradiation [41,59]. Http://www.cancerci.com/content/1/1/1 ther, allowing this extreme shift into the endocycle to occur in the most resistant tumours
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