Radiation-induced cellular senescence results from a slippage of long-term G2 arrested cells into G1 phase

Diploid cells undergoing senescence and mitotic slippage have been reported in the literature. However, the mechanisms triggering senescence in long-term G(2)-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 G(2) phase. We subsequently showed that the genes essential for G(2)-M transition are prematurely downregulated at both the transcriptional and translational levels. Furthermore, levels of the G(1)-specific markers, Cyclin D1 and Caveolin-1, were distinctly increased, while S/G(2)-specific markers, Cyclin B1 and Aurora A, were significantly downregulated. These findings collectively imply that long-term G(2)-arrested cells undergo senescence via G(2) slippage. To our knowledge, this is the first study to report that the cellular process of G(2) slippage is the mechanism responsible for senescence of cells under long-term G(2) arrest.