Exploring the Influence of Parameters on the p53 Response When Single-Stranded Breaks and Double-Stranded Breaks...

Area of Science:

• Cellular biology
• Molecular biology
• Biophysics

Background:

• The p53 protein plays a crucial role in cell fate determination following DNA damage.
• p53 exhibits a preferential response to single-stranded breaks (SSBs) over double-stranded breaks (DSBs).
• The influence of kinetic parameters on this preferential response is not fully understood.

Purpose of the Study:

• To computationally investigate how kinetic parameters affect the p53 response to coexisting SSBs and DSBs.
• To identify specific parameters and their combinations that can alter the natural preferential response of p53.
• To analyze the sensitivity of p53 pulse amplitude and apoptosis to these kinetic parameters.

Main Methods:

• Utilized a hybrid model (model I) for computational analysis.
• Systematically searched the parameter space to identify critical kinetic parameters.
• Analyzed the impact of single and double parameter changes on p53 response dynamics.

Main Results:

• Production rate of ATR (beta2), ATR degradation rate (alf2), and ATR-dependent p53 production (beta31) can alter the graded p53 response to a pulse response.
• Combinations of these parameters with others, and specifically ATM-dependent p53 production rate (beta3) with Wip1-dependent p53 degradation rate (alf35), can modify the natural p53 response.
• Pulse amplitude is most sensitive to ATM-dependent p53 production rate (beta3); apoptosis is sensitive to ATM production rate (beta1), Wip1-dependent ATM degradation (alf15), Wip1 production (beta5), and Wip1 degradation (alf5).

Conclusions:

• Specific kinetic parameters, including those related to ATR and ATM signaling, can modulate the p53 response to DNA damage.
• Understanding these parameter sensitivities offers insights into cellular susceptibility to apoptosis.
• Findings can inform the development of targeted cancer therapies with improved efficacy and reduced toxicity.