A computational model of the DNA damage-induced IKK/ NF-κB pathway reveals a critical dependence on irradiation dose and PARP-1
Year: 2023
Type: article
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
Institutions: Max Delbrück Center, Freie Universität Berlin
Language: English
Topic: NF-κB Signaling Pathways
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,150
Awards: G3584653315, CancerSys-Verbundprojekt: ProSiTu - Quantitative dynamische Modellierung der durch Strahlen- und Chemotherapie aktivierten NF-kappaB und p53 Regulationsnetzwerke in Tumoren und Entwicklung prognostischer Proteom-Signaturen / Teilprojekte 1,2 und 3, e:Med-Modul-II-Verbundprojekt: SeneSys (for iLymTx) - Seneszenz-basierte systemmedizinische Stratifikation zur individualisierten Lymphomtherapie - Teilprojekt D
OpenAlex ID: W4386753006