A Model for p53 Dynamics Triggered by DNA Damage

Several recent experiments on DNA-damage-induced signaling networks in mammalian cells have shown interesting dynamics in p53 protein expression during the repair cycle. Pulses of p53 are produced, whose frequency and amplitude are fairly independent of the amount of damage, but the probability of a cell exhibiting this pulsatile behavior increases with damage. This phenomenon has been described as a “digital oscillator.” We present here a simple model oscillator comprising two species, p53 and Mdm2, which is activated by the Atm kinase. The Atm kinase exhibits bistable switch-like behavior. The network dynamics essentially consists of the core p53 oscillator, which is turned ON/OFF by the Atm switch, which is in turn activated by DNA damage. The complex dynamics are thus explained by the modular nature of the network and are fairly independent of the biological details. A stochastic model of the network dynamics reveals that the pulsatile behavior is robust to intrinsic noise of the protein components and extrinsic noise which arises due to noisy damage signals. The robustness is due to the bistable switch, which makes the system more resilient to stochastic fluctuations in its components. However, the system is more susceptible to noise in the Mdm2 protein production rate.