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Updated: Jun 3, 2025
Techniques to Induce and Quantify Cellular Senescence
Published on: May 1, 2017
The cGAS-STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in
Majd Haj1, Yann Frey1, Amit Levon1
1Department of Human Molecular Genetics and Biochemistry, Faculty of Health & Medical Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Abstract:
Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging. We found that lung fibroblasts derived from ATM-deficient mice provide a versatile experimental system to explore the mechanisms driving the premature senescence of primary fibroblasts lacking ATM. Atm-/- fibroblasts failed to proliferate under ambient oxygen conditions (21%). Although they initially proliferated under physiological oxygen levels (3%), they rapidly entered senescence. In contrast, wild-type (WT) lung fibroblasts did not senesce under 3% oxygen and eventually underwent immortalization and neoplastic transformation. However, rapid senescence could be induced in WT cells either by Atm gene ablation or persistent chemical inhibition of ATM kinase activity, with senescence induced by ATM inhibition being reversible upon inhibitor removal. Moreover, the concomitant loss of ATM and p53 led to senescence evasion, vigorous growth, rampant genome instability, and subsequent immortalization and transformation. Our findings reveal that the rapid senescence of Atm-/- lung fibroblasts is driven by the collaborative action of the cGAS-STING, p38 MAPK, and p53 pathways in response to persistent DNA damage, ultimately leading to the induction of interferon-α1 and downstream interferon-stimulated genes. We propose that accelerated cellular senescence may exacerbate specific A-T symptoms, particularly contributing to the progressive, life-threatening interstitial lung disease often observed in A-T patients during adulthood.
Insights
Ataxia-telangiectasia (A-T) cells lacking ATM undergo rapid senescence due to DNA damage, impacting lung health. Restoring ATM function or inhibiting p53 can prevent this premature aging.
Area of Science:
- Genetics and Molecular Biology
- Cellular Aging and Senescence
- Genomic Instability Syndromes
Background:
- Ataxia-telangiectasia (A-T) is a severe genetic disorder caused by mutations in the ATM gene, leading to a wide range of symptoms including premature aging and cancer predisposition.
- Cellular senescence, a state of irreversible growth arrest, is linked to aging and genome instability, but its precise role in A-T pathogenesis remains unclear.
- Understanding the mechanisms of premature senescence in A-T fibroblasts is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the mechanisms driving premature senescence in ATM-deficient lung fibroblasts.
- To explore the role of ATM, p53, and other signaling pathways in cellular senescence and genome instability.
- To determine the potential contribution of accelerated cellular senescence to A-T-related pathologies, particularly interstitial lung disease.
Main Methods:
- Utilized ATM-deficient (Atm-/-) and wild-type (WT) mouse lung fibroblasts cultured under ambient (21%) and physiological (3%) oxygen conditions.
- Employing gene ablation (Atm knockout) and chemical inhibition of ATM kinase activity to induce senescence in WT cells.
- Investigated the roles of p53, cGAS-STING, and p38 MAPK pathways in senescence induction and evaluated senescence evasion upon combined ATM and p53 loss.
Main Results:
- Atm-/- lung fibroblasts exhibited rapid senescence under both 21% and 3% oxygen, failing to proliferate long-term.
- WT fibroblasts senesced upon Atm gene ablation or ATM inhibition, with ATM inhibition-induced senescence being reversible.
- Concomitant loss of ATM and p53 abrogated senescence, leading to uncontrolled proliferation, genome instability, and transformation, driven by cGAS-STING, p38 MAPK, and p53 pathways.
Conclusions:
- Accelerated senescence in ATM-deficient cells is mediated by persistent DNA damage activating the cGAS-STING, p38 MAPK, and p53 pathways.
- The loss of ATM function, particularly in combination with p53 deficiency, promotes senescence evasion, genomic instability, and neoplastic transformation.
- Premature cellular senescence likely exacerbates A-T symptoms, contributing significantly to the interstitial lung disease observed in patients.
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