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Atypical NF-κB activation by endogenous DNA damage drives senescence and aging

ABSTRACT: Chronic activation of NF-κB contributes to senescence and aging, but how endogenous DNA damage engages this pathway in vivo remains unclear. NF-κB can be activated by an atypical pathway in which genotoxic stress triggers ATM-dependent sumoylation of the regulatory subunit NEMO, yet the role of this axis in senescence and aging has not been tested. Here we introduced a knock-in NEMO double-lysine mutant (NEMO-DK) that prevents sumoylation at the conserved sites required for DNA damage-induced NF-κB activation, and examined its impact in Ercc1-/∆ mice, a model of accelerated, DNA damage-driven aging. We demonstrated that NEMO-DK markedly reduced senescence and SASP in primary fibroblasts and across multiple tissues, improved liver and skeletal muscle pathology, attenuated intervertebral disc degeneration, significantly delayed the onset and progression of aging symptoms and extended healthspan. These findings identify DNA damage-induced NEMO sumoylation as a key driver of NF-κB-mediated senescence in vivo and suggest that the atypical NF-κB pathway is a potential therapeutic target to mitigate aging-associated diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE314144 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Kollarovic2016 - Cell fate decision at G1-S transition This model is described in the article: To senesce or not to senesce: how primary human fibroblasts decide their cell fate after DNA damage. Kollarovic G, Studencka M, Ivanova L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS, Schaber J. Aging (Albany NY) 2016 Jan; Abstract: Excessive DNA damage can induce an irreversible cell cycle arrest, called senescence, which is generally perceived as an important tumour-suppressor mechanism. However, it is unclear how cells decide whether to senesce or not after DNA damage. By combining experimental data with a parameterized mathematical model we elucidate this cell fate decision at the G1-S transition. Our model provides a quantitative and conceptually new understanding of how human fibroblasts decide whether DNA damage is beyond repair and senesce. Model and data imply that the G1-S transition is regulated by a bistable hysteresis switch with respect to Cdk2 activity, which in turn is controlled by the Cdk2/p21 ratio rather than cyclin abundance. We experimentally confirm the resulting predictions that to induce senescence i) in healthy cells both high initial and elevated background DNA damage are necessary and sufficient, and ii) in already damaged cells much lower additional DNA damage is sufficient. Our study provides a mechanistic explanation of a) how noise in protein abundances allows cells to overcome the G1-S arrest even with substantial DNA damage, potentially leading to neoplasia, and b) how accumulating DNA damage with age increasingly sensitizes cells for senescence. This model is hosted on BioModels Database and identified by: BIOMD0000000632. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Atypical NF-κB activation by endogenous DNA damage drives senescence and aging

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