Activation of p53 in G₂ Phase Irreversibly Primes Cells for Senescence

Antiproliferative stimuli such as DNA damage and oncogenic stress can lead to permanent cell-cycle exit and senescence, which represents an important barrier to tumorigenesis. However, the regulation of cell fate and the mechanisms that trigger senescence in different phases of the cell cycle remain unclear, prompting Krenning and colleagues to monitor cell-cycle dynamics in individual nontransformed cells following DNA damage. In contrast to G₁ cells, cells damaged in G₂ phase rapidly lost proliferative capacity following irradiation, failed to enter mitosis, and underwent irreversible cell-cycle withdrawal. DNA damage–induced senescence was dependent on p53- and p21-dependent nuclear retention of cyclin B1, which led to its degradation via premature activation of the anaphase-promoting complex/cyclosome and its coactivator Cdh1 (APC/C^Cdh1) and occurred in an IR and p21 dose-dependent manner, suggesting that a threshold of damage must be met prior to permanent cell-cycle exit. Indeed, transient induction of p53 activity in G₂ cells was sufficient to drive nuclear cyclin B1 retention and to block mitotic entry. Consistent with these findings, Johmura and colleagues showed that genotoxic and oncogenic stress in G₂ phase promoted mitotic skipping in normal human diploid fibroblasts, which was necessary and sufficient for senescence induction and generated tetraploid G₁ cells. In addition to p53/p21-mediated premature APC/C^Cdh1 activation, this mitotic skip also required p53-dependent activation of pRB family pocket proteins, which transcriptionally repressed mitotic regulators; however, p16 was required only for maintenance of the senescent state. In support of the role of mitotic bypass in vivo, human nevus cells, which typically harbor oncogenic RAS signaling, displayed increased DNA content in the absence of proliferation and cyclin B1 expression. Together, these results suggest that p53 activity during G₂ phase irreversibly primes cells for mitotic bypass and senescence induction via p21- and pRB-mediated mechanisms.

Krenning L, Feringa FM, Shaltiel IA, van den Berg J, Medema RH. Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell 2014 Jun 5 [Epub ahead of print].

Johmura Y, Shimada M, Misaki T, Naiki-Ito A, Miyoshi H, Motoyama N, et al. Necessary and sufficient role for a mitosis skip in senescence induction. Mol Cell 2014 Jun 5 [Epub ahead of print].