Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Drosophila Endocycling Cells
In mitotic cycling cells, genotoxic stress activates ATM kinase to phosphorylate Chk2, which in turn phosphorylates p53, resulting in transcriptional activation of the H99 genes. Our data suggest that p53 protein stability in these cells is regulated and tunes a threshold level of p53A protein that induces apoptosis only in response to stress. In addition, our data indicate that p53A protein and a paused RNA Pol II are bound to the H99 promoters in the absence of stress. Preloading of p53A and RNA Pol II may prepare these promoters for a rapid stress response. At later time points, p53-independent pathways also mediate cell death through transcriptional activation of H99 genes. In the endocycling cells, ATM kinase is activated, but p53 protein levels are low, p53A is targeted for degradation by the proteasome, and the promoter-enhancer regions of the H99 genes are epigenetically silenced, further blocking their activation by p53-dependent as well as p53-independent cell death pathways. Together, these mechanisms enforce a tight repression of the apoptotic response to genotoxic stress in endocycling cells.