Proceedings of the National Academy of Sciences of the United States of AmericaJan 8, 2025

How DNA damage triggers faster cell aging through specific stress and repair pathways in lung cells lacking ATM

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Updated Apr 5, 2026

Abstract

Lung fibroblasts from ATM-deficient mice fail to proliferate under normal oxygen levels.

ATM-deficient lung fibroblasts initially proliferate in low oxygen (3%) but quickly enter premature senescence.
Wild-type fibroblasts do not senesce under the same low oxygen conditions and can become immortalized.
Inducing ATM inhibition in wild-type cells leads to rapid senescence, which can be reversed upon removal of the inhibitor.
Loss of both ATM and p53 allows cells to evade senescence, resulting in aggressive growth and genome instability.
The rapid senescence in ATM-deficient fibroblasts is linked to specific cellular pathways responding to DNA damage.
Accelerated may worsen certain symptoms of , especially interstitial lung disease.

Simplified

(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, , 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.-/- 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 bygene 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-/- 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. Atm Atm Atm

Key numbers

8 of 8 passages

Growth Limitation

ATM-deficient fibroblasts halted growth at passage level 8.

γH2AX foci

Increased DNA Damage

Elevated levels of γH2AX foci indicate significant DNA damage in ATM-deficient fibroblasts.

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How DNA damage triggers faster cell aging through specific stress and repair pathways in lung cells lacking ATM

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