Radiation-induced cellular senescence results from a slippage of long-term G₂arrested cells into G₁phase

Abstract

Diploid cells undergoing senescence and mitotic slippage have been reported in the literature. However, the mechanisms triggering senescence in long-term G2-arrested cells are currently unclear. Previously, we reported that the cell cycle of the human uveal melanoma cell line, 92-1, is suspended for up to 6 d upon exposure to 10 Gy ionizing radiation (IR), followed by senescence. In the current study, we initially distinguished senescence in long-term blocked 92-1 cells from mitotic slippage by confirming the blockage of cells in the G2 phase. We subsequently showed that the genes essential for G2-M transition are prematurely downregulated at both the transcriptional and translational levels. Furthermore, levels of the G1-specific markers, Cyclin D1 and Caveolin-1, were distinctly increased, while S/G2-specific markers, Cyclin B1 and Aurora A, were significantly downregulated. These findings collectively imply that long-term G2-arrested cells undergo senescence via G2 slippage. To our knowledge, this is the first study to report that the cellular process of G2 slippage is the mechanism responsible for senescence of cells under long-term G2 arrest.

Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction

“…In contrast, the accumulation of G2 phase cells during replicative senescence has also been reported, arguing against the senescence model described above (Mao et al, 2012;Ye et al, 2013). In addition, p21-mediated inhibition of Cdk1 and Cdk2 was proposed to prematurely activate APC/C Cdh1 to destroy various APC/C substrates, resulting in long-term growth arrest at G2 in response to genotoxic stress (Baus et al, 2003;Wiebusch and Hagemeier, 2010).…”

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

“…4A) (Johmura et al, 2014;Krenning et al, 2014;Lee et al, 2009;Lindqvist et al, 2009b;Wiebusch and Hagemeier, 2010). The resulting cells that have a G2 DNA content but lack G2-specific protein expression are committed to senescence (Johmura et al, 2014;Ye et al, 2013). In order for a G2 arrest to remain reversible, Cdk activity must thus be maintained at sufficient levels to preserve pro-mitotic gene transcription, but also to prevent premature activation of the APC/C.…”

Senescence from G2 arrest, revisited

“…showed that radiation-induced cellular senescence results from mitotic bypass of stably G2-arrested cells into a tetraploid G1 phase, where they accumulate cyclin D1. 90 Conversely, in p53/pRb-deficient MEFs, DNA damage generated by persistent telomere dysfunction induces prolonged G2 arrest that leads to genome reduplication and tetraploidy due to the absence of the p53/p21-dependent G1/S checkpoint ( Fig. 3; 88 ).…”