Frequency Domain Analysis Reveals External Periodic Fluctuations Can Generate Sustained p53 Oscillation

p53 is a well-known tumor suppressor protein that regulates many pathways, such as ones involved in cell cycle and apoptosis. The p53 levels are known to oscillate without damping after DNA damage, which has been a focus of many recent studies. A negative feedback loop involving p53 and MDM2 has been reported to be responsible for this oscillatory behavior, but questions remain as how the dynamics of this loop alter in order to initiate and maintain the sustained or undamped p53 oscillation. Our frequency domain analysis suggests that the sustained p53 oscillation is not completely dictated by the negative feedback loop; instead, it is likely to be also modulated by periodic DNA repair-related fluctuations that are triggered by DNA damage. According to our analysis, the p53-MDM2 feedback mechanism exhibits adaptability in different cellular contexts. It normally filters noise and fluctuations exerted on p53, but upon DNA damage, it stops performing the filtering function so that DNA repair-related oscillatory signals can modulate the p53 oscillation. Furthermore, it is shown that the p53-MDM2 feedback loop increases its damping ratio allowing p53 to oscillate at a frequency more synchronized with the other cellular efforts to repair the damaged DNA, while suppressing its inherent oscillation-generating capability. Our analysis suggests that the overexpression of MDM2, observed in many types of cancer, can disrupt the operation of this adaptive mechanism by making it less responsive to the modulating signals after DNA damage occurs.