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PreprintCited by 7NF-κB Signaling PathwaysDNA Repair MechanismsGene Regulatory Network Analysis

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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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Konrath, Fabian, Willenbrock, Michael, Busse, Dorothea, Scheidereit, Claus, Wolf, Jana·2023·iScience
DOI 10.1101/2023.05.02.538686PMC PMC10561052

Preprint — published as 10.1016/j.isci.2023.107917 · Paper page

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Abstract

Summary: 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 tumour therapy-induced cell death. Here, we developed a dynamical model describing IKK/ NF-κB 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.

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Metadata

Authors
Konrath, F., Willenbrock, M., Busse, D., Scheidereit, C., & Wolf, J.
Affiliations
Max Delbrück Center (DE)
Corresponding author
Wolf, Jana
ORCID
Venue
iScience
Publisher
openRxiv
Published
2023-05-02
Volume
26
Issue
10
Pages
107917-107917
ISSN
2589-0042 (ISSN-L)
DOI
10.1101/2023.05.02.538686
PMC
PMC10561052
OpenAlex
W4386753006
Cited by
7
References
1
Citations by year
2026: 2 · 2025: 1 · 2024: 3 · 2023: 1
FWCI
0.89
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • iScience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (Graduiertenkolleg 1772)
  • Bundesministerium für Bildung und Forschung (0316047A, 031L0189D)
  • Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
IKK/NF-κB signaling, DNA damage response, PARP1, radiation dose dependence, signal integration, pathway topology, dynamic modeling, genotoxic stress, anti-apoptotic signaling

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