A computational model of the DNA damage-induced IKK/ NF-κB pathway reveals a critical dependence on irradiation dose and PARP-1

Fabian Konrath; Michael Willenbrock; Dorothea Busse; Claus Scheidereit; Jana Wolf

doi:10.1016/j.isci.2023.107917

A computational model of the DNA damage-induced IKK/ NF-κB pathway reveals a critical dependence on irradiation dose and PARP-1

iScience. 2023 Sep 14;26(10):107917. doi: 10.1016/j.isci.2023.107917. eCollection 2023 Oct 20.

Authors

Fabian Konrath¹, Michael Willenbrock², Dorothea Busse¹, Claus Scheidereit², Jana Wolf^{1

3}

Affiliations

¹ Mathematical Modelling of Cellular Processes, Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
² Laboratory for Signal Transduction in Tumor Cells, Max Delbrueck Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
³ Department of Mathematics and Computer Science, Free University Berlin, Germany.

Abstract

The activation of IKK/NF-κB by genotoxic stress is a crucial process in the DNA damage response. Due to the anti-apoptotic impact of NF-κB, it can affect cell-fate decisions upon DNA damage and therefore interfere with tumor therapy-induced cell death. Here, we developed a dynamical model describing IKK/NF-κB signaling that faithfully reproduces quantitative time course data and enables a detailed analysis of pathway regulation. The approach elucidates a pathway topology with two hubs, where the first integrates signals from two DNA damage sensors and the second forms a coherent feedforward loop. The analyses reveal a critical role of the sensor protein PARP-1 in the pathway regulation. Introducing a method for calculating the impact of changes in individual components on pathway activity in a time-resolved manner, we show how irradiation dose influences pathway activation. Our results give a mechanistic understanding relevant for the interpretation of experimental and clinical studies.

Keywords: Experimental models in systems biology; Systems biology.