The role of p21 in G2 cell cycle arrest in response to DNA damage

Cell cycle arrest is a critical defense tactic in response to DNA damage as it allows time for DNA repair or induction of apoptosis. When a cell cannot efficiently induce cell cycle arrest, the result is the inappropriate progression through the cell cycle and the accumulation of mutated or damaged DNA. The p53-activated gene p21Cip1/WAF1 is the principal mediator of cell cycle arrest in response to DNA damage. Cancer cells unable to mediate cell cycle arrest in response to DNA damage (cells lacking functional p53 or p21) are more sensitive to cell death and thus have a heightened sensitivity to DNA-damaging cancer therapeutics (i.e.: chemotherapies and radiation).;p21, a cyclin-dependent kinase inhibitor, has long been demonstrated to play a critical role in G1 cell cycle arrest in response to DNA damage through its interaction with G1-associated cyclin/Cdk complexes. Work described in this thesis suggests that p21 may also play a significant role in G2 cell cycle arrest. Experiments demonstrate that in response to DNA damage G2 cell cycle arrest is aided by the p21-mediated degradation of the G2-associated cyclin, cyclin B1. Cells lacking or impaired in the ability to upregulate p21 in response to DNA damage are unable to mediate the degradation of cyclin B1, cannot sustain G2 cell cycle arrest and eventually succumb to cell death. Cell death primarily occurs through mitotic catastrophe resulting from aberrant entry into M phase in the presence of DNA damage. Furthermore, preliminary experiments suggest p21 may play a direct role in mediating cyclin B1 degradation. In conclusion, these results suggest p21-mediated cyclin B1 degradation is necessary to sustain G2 cell cycle arrest and protect cells from death in response to DNA damage.