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Mitotic death: a mechanism of survival? A review
Jekaterina Erenpreisa1, M S Cragg
1Laboratory of Tumour Cell Biology, Biomedicine Centre of the Latvian University, Latvia. katrina@biomed.lu.lv
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.
Insights
Mitotic death in p53 mutant tumors is a delayed survival mechanism. These cells adapt checkpoints to repair DNA, potentially leading to resistance against genotoxic damage.
Area of Science:
- Cell Biology
- Cancer Biology
- Genetics
Background:
- p53 mutant tumors exhibit delayed mitotic death, a response to genotoxic damage.
- The survival function and delayed mechanisms of this response remain unclear.
- Tumor cells adapt cell cycle checkpoints (G1, S) to facilitate survival.
Purpose of the Study:
- To investigate the delayed mechanisms of mitotic death in p53 mutant tumors.
- To understand how these mechanisms contribute to tumor cell survival and genotoxic resistance.
Main Methods:
- Analysis of cell cycle progression and checkpoint adaptation in p53 mutant cells.
- Investigation of DNA repair pathways (homologous recombination) during G2 arrest.
- Characterization of cell fate decisions (apoptosis, endocycles, mitotic death) following genotoxic stress.
Main Results:
- p53 mutant cells bypass G1/S arrests, accumulating DNA damage before G2.
- Cells in G2 arrest can repair double-strand breaks or undergo mitotic death.
- Mitotic death involves apoptosis and mitosis restitution, enabling endocycles and potential survival progeny.
Conclusions:
- Mitotic death features indicate a switch to amitotic survival strategies in p53 mutant cells.
- These adaptive mechanisms enhance genotoxic resistance.
- Endocycling during G2 arrest and mitosis restitution facilitates DNA repair and potential propagation.