Cooperative effects of genes controlling the G₂/M checkpoint

It is believed that multiple effectors independently control the checkpoints permitting transitions between cell cycle phases. However, this has not been rigorously demonstrated in mammalian cells. The p53-induced genes p21 and 14-3-3σ are each required for the G₂ arrest and allow a specific test of this fundamental tenet. We generated human cells deficient in both p21 and 14-3-3σ and determined whether the double knockout was more sensitive to DNA damage than either single knockout. p21(-/-) 14-3-3σ(-/-) cells were significantly more sensitive to DNA damage or to the exogenous expression of p53 than cells lacking only p21 or only 14-3-3σ. Thus, p21 and 14-3-3σ play distinct but complementary roles in the G₂/M checkpoint, and help explain why genes at the nodal points of growth arrest pathways, like p53, are the targets of mutation in cancer cells.