New Insights into p53 Signaling and Cancer Cell Response to DNA Damage: Implications for Cancer Therapy

Figure 7

ATM-p53-p21 signaling in p53 wild-type human solid tumor-derived cells exposed to ionizing radiation. (a) Radiation exposure results in ATM-dependent activation of several proteins (e.g., p53, WRN, DNA-PKcs) that play important roles in DSB repair, as well as p53-mediated activation of p21 that suppresses apoptosis and activates cell cycle checkpoints. Proper activation of these early events provides time for the repair of potentially cytotoxic and mutagenic lesions. (b) Persistence of DNA damage (i.e., irreparable damage) at late times (several days) after irradiation leads to sustained induction of p21 which suppresses apoptosis and triggers SIPS. Positive feedback loops between ATM and p53 and between p53 and p21 ensure the maintenance of the SIPS response for extended times (several months in culture). WRN, Werner’s syndrome protein; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; γ-H2AX, H2A variant histone H2AX phosphorylated on Ser 139.