Haj Majd, Frey Yann, Levon Amit, Maliah Avishai, Ben-Yishay Tal, Slutsky Rachel, Smoom Riham, Tzfati Yehuda, Ben-David Uri, Levy Carmit, Elkon Ran, Ziv Yael, Shiloh Yosef
Department of Human Molecular Genetics and Biochemistry, Faculty of Health & Medical Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190501, Israel.
Proc Natl Acad Sci U S A. 2025 Jan 14;122(2):e2419196122. doi: 10.1073/pnas.2419196122. Epub 2025 Jan 7.
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. -/- 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 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 -/- 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.
共济失调毛细血管扩张症（A-T）是一种多效性基因组不稳定综合征，由稳态蛋白激酶ATM缺失所致。A-T的复杂表型包括进行性小脑变性、免疫缺陷、性腺萎缩、间质性肺病、癌症易感性、内分泌异常、染色体不稳定、放射敏感性和节段性早衰。A-T患者的培养皮肤成纤维细胞表现出早衰，凸显了基因组不稳定、细胞衰老和衰老之间的关联。我们发现，源自ATM缺陷小鼠的肺成纤维细胞提供了一个通用的实验系统，以探索驱动缺乏ATM的原代成纤维细胞早衰的机制。-/-成纤维细胞在环境氧条件（21%）下无法增殖。尽管它们最初在生理氧水平（3%）下增殖，但很快进入衰老状态。相比之下，野生型（WT）肺成纤维细胞在3%氧气条件下不会衰老，最终发生永生化和肿瘤转化。然而，通过基因敲除或持续化学抑制ATM激酶活性可在WT细胞中诱导快速衰老，去除抑制剂后，由ATM抑制诱导的衰老可逆。此外，ATM和p53的同时缺失导致衰老逃避、旺盛生长、猖獗的基因组不稳定，随后发生永生化和转化。我们的研究结果表明，-/-肺成纤维细胞的快速衰老是由cGAS-STING、p38 MAPK和p53途径对持续性DNA损伤的协同作用驱动的，最终导致干扰素-α1和下游干扰素刺激基因的诱导。我们提出，加速的细胞衰老可能会加重A-T的特定症状，特别是导致A-T患者成年期经常出现的进行性、危及生命的间质性肺病。
