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

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 interpathway 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 method for calculating the impact of changes in individual components on pathway activity in a timeresolved manner, we show how irradiation dose influences pathway activation. Our results give a mechanistic understanding relevant for the interpretation of experimental and clinical studies.