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bioRxiv · 10.1101/2023.05.02.538686

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

Konrath, F.·Willenbrock, M.·Busse, D.·Scheidereit, C.·Wolf, J.
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Abstract

The activation of IKK/ NF-{kappa}B by genotoxic stress is a crucial process in the DNA damage response. Due to the anti-apoptotic impact of NF-{kappa}B it can affect cell fate decisions upon DNA damage and therefore interfere with tumour therapy-induced cell death. Here, we developed a dynamical model describing IKK/ NF-{kappa}B signalling that faithfully reproduces quantitative time course data and enabled 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 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/538686v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@5ba82borg.highwire.dtl.DTLVardef@17dc530org.highwire.dtl.DTLVardef@1cf6fborg.highwire.dtl.DTLVardef@19ae207_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Konrath, F., Willenbrock, M., Busse, D., Scheidereit, C., Wolf, J.. 2023-05-02. A computational model of the DNA damage-induced IKK/ NF-κB pathway reveals a critical dependence on irradiation dose and PARP-1. https://doi.org/10.1101/2023.05.02.538686

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