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

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Item Type:Article
Title:A computational model of the DNA damage-induced IKK/ NF-κB pathway reveals a critical dependence on irradiation dose and PARP-1
Creators Name:Konrath, F., Willenbrock, M., Busse, D., Scheidereit, C. and Wolf, J.
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.
Source:iScience
ISSN:2589-0042
Publisher:Cell Press
Volume:26
Number:10
Page Range:107917
Date:20 October 2023
Official Publication:https://doi.org/10.1016/j.isci.2023.107917
PubMed:View item in PubMed

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