A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence

• Published in: PLoS computational biology Vol. 13; no. 12; p. e1005741
• Main Authors: Meyer, Patrick, Maity, Pallab, Burkovski, Andre, Schwab, Julian, Müssel, Christoph, Singh, Karmveer, Ferreira, Filipa F, Krug, Linda, Maier, Harald J, Wlaschek, Meinhard, Wirth, Thomas, Kestler, Hans A, Scharffetter-Kochanek, Karin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.12.2017; Public Library of Science (PLoS)
• Subjects: Aging; Aging (Biology); Animals; Biological effects; Biology; Biology and life sciences; Boolean algebra; Cancer; Cell cycle; Cells, Cultured; Cellular Senescence - physiology; Computational Biology; Computer and Information Sciences; Computer Simulation; Cytokines; Damage prevention; Deoxyribonucleic acid; Dermatology; DNA; DNA damage; DNA Damage - physiology; Fibroblasts; Funding; Genetic aspects; Genotype & phenotype; Immunology; Inflammation; Interleukin 6; Interleukin 8; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - metabolism; Interleukin-8 - antagonists & inhibitors; Interleukin-8 - metabolism; Kinases; Medicine and Health Sciences; Mice; Models, Biological; NF-κB protein; Phosphorylation; Physiological aspects; Proteins; Senescence; Signal transduction; Signal Transduction - physiology; Signaling; Skin; Software; Tissues
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1005741

Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases.