Figure 1.

Impaired p53-mediated transcriptional response during S-phase blockade in the absence or presence of additional concomitant DNA damaging exposures. In the case of cycling cells, double-strand breaks lead to p53 stabilization through the activation of ATM and Chk1 kinases. Stabilized and activated p53 binds to the regulatory regions of target genes, which mediate its effects (Left). However, when cells are blocked in S-phase, p53 fails to induce some of its target genes even though it is stabilized (Right). Moreover, even x-ray irradiation cannot restore the transcriptional activation of p53 despite phosphorylation, acetylation, and stabilization of p53. ATR and Hus1 are conserved PI-3 kinase-like and PCNA-like, respectively, proteins that have been implicated in the cellular response to UV exposure and replication blockade (11). p53RE, consensus p53 DNA binding sites; HU and APH, hydroxyurea and aphidicolin, respectively.