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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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.
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Cites
Global quantification of mammalian gene expression control
Schwanhäusser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., & Selbach, M. (2011) · Nature · doi:10.1038/nature10098 · Cited by 6,566 · cited 2× · see citing works
“In summary, inhibition of ATM activation can reduce the level of activated IKK complex in the stimulated steady state by limiting the availability of PARylated PARP-1 and thereby reducing the flux of signalosome formation and consequently the amount of modified IKK g .”
BackgroundSelf-citationRaue, A., Kreutz, C., Maiwald, T., Bachmann, J., Schilling, M., Klingmüller, U., & Timmer, J. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp358 · Cited by 1,442 · see citing works
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
Hinz, M., Stilmann, M., Arslan, S. Ç., Khanna, K. K., Dittmar, G., & Scheidereit, C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.008 · Cited by 280 · see citing works
Self-citationBeyond IκBs: alternative regulation of NF‐KB activity
Neumann, M., & Naumann, M. (2007) · The FASEB Journal · doi:10.1096/fj.06-7615rev · Cited by 267 · see citing works
Fröhlich, F., Kessler, T., Weindl, D., Shadrin, A., Schmiester, L., Hache, H., Muradyan, A., Schütte, M., Lim, J.-H., Heinig, M., et al. (2018) · Cell Systems · doi:10.1016/j.cels.2018.10.013 · Cited by 143 · see citing works
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- Authors
- Konrath, F., Willenbrock, M., Busse, D., Scheidereit, C., & Wolf, J.
- Affiliations
- Max Delbrück Center (DE)
- Corresponding author
- Wolf, Jana
- Venue
- iScience
- Publisher
- Elsevier BV
- Published
- 2023-10
- Volume
- 26
- Issue
- 10
- Pages
- 107917
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC10561052
- OpenAlex
- W4386753006
- Cited by
- 7
- References
- 6
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 1
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- 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)
- BMBF Berlin
- Bundesministerium für Bildung und Forschung (0316047A, 031L0189D)
- 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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