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Updated: Mar 22, 2026
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
IFI16, an amplifier of DNA-damage response: Role in cellular senescence and aging-associated inflammatory diseases
Divaker Choubey1, Ravichandran Panchanathan1
1Cincinnati VA Medical Center, 3200 Vine Street, Cincinnati, OH 45220, United States; Department of Environmental Health, University of Cincinnati, 160 Panzeca Way, P.O. Box-670056, Cincinnati, OH 45267, United States.
Abstract:
DNA-damage induces a DNA-damage response (DDR) in mammalian cells. The response, depending upon the cell-type and the extent of DNA-damage, ultimately results in cell death or cellular senescence. DDR-induced signaling in cells activates the ATM-p53 and ATM-IKKα/β-interferon (IFN)-β signaling pathways, thus leading to an induction of the p53 and IFN-inducible IFI16 gene. Further, upon DNA-damage, DNA accumulates in the cytoplasm, thereby inducing the IFI16 protein and STING-dependent IFN-β production and activation of the IFI16 inflammasome, resulting in the production of proinflammatory cytokines (e.g., IL-1β and IL-18). Increased expression of IFI16 protein in a variety of cell-types promotes cellular senescence. However, reduced expression of IFI16 in cells promotes cell proliferation. Because expression of the IFI16 gene is induced by activation of DNA-damage response in cells and increased levels of IFI16 protein in cells potentiate the p53-mediated transcriptional activation of genes and p53 and pRb-mediated cell cycle arrest, we discuss how an improved understanding of the role of IFI16 protein in cellular senescence and associated inflammatory secretory phenotype is likely to identify the molecular mechanisms that contribute to the development of aging-associated human inflammatory diseases and a failure to cancer therapy.
Insights
DNA-damage response (DDR) activates signaling pathways, inducing IFI16 protein. This protein influences cellular senescence and proliferation, impacting aging-associated diseases and cancer therapy failure.
Area of Science:
- Cellular Biology
- Molecular Biology
- Immunology
Background:
- DNA-damage triggers a DNA-damage response (DDR) in mammalian cells, leading to cell death or senescence.
- DDR activates ATM-p53 and ATM-IKKα/β-interferon (IFN)-β pathways, inducing p53 and IFN-inducible IFI16 gene expression.
Purpose of the Study:
- To investigate the role of IFI16 protein in cellular senescence and the inflammatory secretory phenotype.
- To explore how IFI16 influences aging-associated inflammatory diseases and cancer therapy resistance.
Main Methods:
- Analysis of DDR-induced signaling pathways.
- Assessment of IFI16 protein expression and its impact on cellular senescence and proliferation.
- Investigation of cytoplasmic DNA accumulation and its role in IFI16 and IFN-β production.
Main Results:
- DNA-damage induces IFI16 gene and protein expression via DDR.
- Cytoplasmic DNA accumulation upon damage activates STING-dependent IFN-β production and the IFI16 inflammasome, leading to pro-inflammatory cytokine release.
- Increased IFI16 promotes senescence, while reduced IFI16 promotes proliferation.
Conclusions:
- IFI16 protein plays a dual role in cell fate decisions following DNA damage, influencing senescence and proliferation.
- Understanding IFI16's role in senescence and inflammation is crucial for developing strategies against aging-associated inflammatory diseases and overcoming cancer therapy failure.
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