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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. and Willenbrock, M. and Busse, D. and 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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