Mathematical Modeling of Nf-Kappab and P53 Signaling in the DNA Damage Response

By Fabian Konrath

Cells are permanently challenged by DNA damage which can be induced by environmental factors such as UV irradiation or intracellular factors like reactive oxygen species. As damaged DNA can lead to malignant transformations, a complex signaling network termed DNA damage response is activated upon detection of DNA lesions and allows to maintain genomic integrity. The two transcription factors NF-kappaB and p53 regulate cell fate decisions upon genotoxic stress and therefore play crucial roles in the DNA damage response. To investigate the regulation of NF-kappaB activity, a mathematical model of coupled ordinary differential equations was developed and analyzed. The model describes DNA damage-induced activation of NF-kappaB and quantitatively reproduces multiple experimental data sets. Analyzing the time-resolved regulation of NF-kappaB revealed regulatory mechanisms of DNA damage-dependent NF-kappaB signaling and allowed the evaluation of drug targets inhibiting NF-kappaB activity. Further, the interplay of NF-kappaB and p53 signaling was investigated by developing a mathematical modeling framework to systematically identify interfaces between the NF-kappaB and p53 network. NF-kappaB signaling was perturbed and the resulting changes in single cell dynamics of p53 upon genotoxic stress were captured. By fitting a pool of subpopulation-specific ordinary differential equation models to the single cell data, one of the first quantitative p53 models reproducing the heterogeneous dynamics of p53 was developed. Based on the observed changes in p53 dynamics, the results of the modeling framework indicate that NF-kappaB signaling interferes with the activation and degradation of p53 as well as the degradation of its inhibitor Mdm2. Taken together, the results in this work give new insights into the regulation of genotoxic NF-kappaB and p53 signaling and highlight the complexity of their crosstalk.

• Format: Paperback
• Language: English
• ISBN: 3832551360
• ISBN13: 9783832551360
• Release Date: July 2020
• Publisher: Logos Verlag Berlin
• Length: 251 Pages
• Weight: 1.12 lbs.