Escaping death to quiescence: avoiding mitotic catastrophe after DNA damage.

When a mammalian cell exits G1 and enters the S-phase, it becomes committed to the completion of the entire cell cycle until the next G1 phase, where a quiescent status can be reached. However, when DNA damage is induced, mammalian cells may activate checkpoints that arrest the cell cycle during specific phases, such as G1, intra-S, and G2. The mechanisms dictating the exit from cycle arrest have major implications on cell fate and thus affect the outcome of DNA damage-based cancer therapies.

In one scenario, cells can recover from temporary arrest after DNA damage is repaired. This results in the resumption of cell cycle progression, although a fraction of the surviving cells may contain an altered genome due to mutagenic DNA repair. In another scenario, cells escape cycle arrest with residual DNA damage. This can lead to delayed cell death or genomic instability. Following release from G2 arrest, such events have the potential to induce cell death through mitotic catastrophe. Lastly, permanently arrested cells have the option to enter a quiescent G1/G0 status known as senescence. It is not difficult to see how long-term G1 arrest permits entrance into senescence, but it is unclear how G2-arrested cell can enter this state.

In a recent article, Ye et al. reported that the induction of long-term G2 arrest resulted in the complete omission of M-phase and facilitated the entrance into a tetraploid quiescent G1 phase. The investigators used a cell line that was previously shown to be able to undergo long-term G2 arrest after a high dose of ionizing radiation. They found that after 10 Gy of γ-irradiation, these cells underwent a long-term G2 arrest, which was never followed by mitosis. Critical genes involved in the G2-M transition were downregulated in the G2-arrested cells. Furthermore, these tetraploid quiescent cells displayed a senescent phenotype. This led to the conclusion that these G2-arrested cells directly bypassed mitosis and entered into a G1/G0 quiescent status. This is the first report that suggests G2 arrest induced by DNA damage can result in G2 slippage that bypasses mitosis, although it has been previously reported that long-term arrest at metaphase causes the abortion of mitosis (mitotic slippage) and subsequent entrance into G1.

Unlike G1 phase, G2 phase is only a transient phase of the cell cycle. It is conceivable that if the damaged cells adapt to the long-term G2 arrest and prematurely enter mitosis with DNA damage, mitotic catastrophe is likely the outcome. Therefore, G2 slippage might be a mechanism for the cells to escape reproductive mitotic death to enter a quiescent status in the event of severe DNA damage at G2 or late S phase. The study by Ye et al. raises several questions relevant to radiation cancer therapy.

First, DNA damage induced senescence is considered to be a form of accelerated cellular senescence (ACS). The ACS cells retain some metabolic activities, but a small portion of the ACS cells may reenter the cell cycle. The senescent tetraploid G1 cells observed by Ye et al. were induced by a high dose of radiation and may be considered a form of ACS. It remains to be determined whether a small fraction of the tetraploid ACS cells formed after G2 slippage reentered the cell cycle, as this has significant implications for cancer therapy.

Second, a major mechanism of radiation induced proliferative cell death is through mitotic catastrophe. It was noted that the long-term G2 arrest and subsequent senescence by G2 slippage is more predominant at a high dose of irradiation than at a modest dose., This raises the interesting question of whether G2 slippage is a predominant outcome after high dose irradiation. The answer to this question would be relevant to the emerging concept of high dose stereotactic ablative radiotherapy., High doses could efficiently induce senescence that would quickly control tumor mass, but it would also enable cells to avoid cell death via mitotic catastrophe. Thus, ablative radiotherapy would be beneficial for the initial and local control of tumor mass, but it may also leave the possibility of tumor recurrence, because a small fraction of the therapy induced ACS cells may re-enter the cell cycle.