Computational modelling identifies primary mediators of crosstalk between DNA damage and oxidative stress responses

Area of Science:

• Cellular biology
• Computational toxicology
• Systems biology

Background:

• Cells activate multiple stress pathways, including oxidative stress response (OSR) and DNA damage response (DDR), upon toxicant exposure.
• Crosstalk between OSR and DDR pathways is known to influence cellular fate and adverse reactions.
• Understanding this crosstalk is crucial for predicting cellular responses to drugs and toxicants.

Purpose of the Study:

• To develop computational models describing the dynamics of OSR and DDR proteins in liver cells (HepG2) in vitro.
• To identify key interactions driving crosstalk between OSR and DDR pathways.
• To assess the importance of these interactions in protein dynamics and potential adversity prediction.

Main Methods:

• Developed a new computational model for the OSR pathway and coupled it with an existing DDR pathway model.
• Extended the combined model to incorporate literature-described crosstalk mechanisms.
• Applied the models to time-dynamic data of OSR (NRF2, SRXN1) and DDR (p53, p21, BTG2, MDM2) proteins in HepG2 cells exposed to diethyl maleate or etoposide.
• Performed in silico knockdowns of key model components.

Main Results:

• The developed computational models accurately described key OSR and DDR protein dynamics in HepG2 cells.
• In silico knockdowns generally showed moderate effects on the connected pathways.
• Knockdown of p21 significantly reduced levels of NRF2 and SRXN1, indicating a substantial impact on the OSR pathway.

Conclusions:

• The computational models successfully capture the interplay between OSR and DDR pathways.
• The p21 protein plays a critical role in mediating crosstalk between DDR and OSR.
• These models have potential applications in predicting cellular adversity by integrating with cell fate prediction models.