An interferon-like response links genome instability to accelerated cellular senescence
in murine Atm-deficient lung fibroblasts

The genetic syndrome, ataxia-telangiectasia (A-T), links genome instability to tissue degeneration, cancer predisposition and premature aging. A-T is caused by loss of the protein kinase, ATM - a chief mobilizer of the DNA damage response. Here, we show that, under physiological oxygen concentration, murine Atm-/- lung fibroblasts undergo accelerated senescence, while WT cells never senesce. Accordingly, rapid senescence was induced in WT cells by ablation of their Atm gene. Concomitant loss of the p53 protein rescued the rapid senescence caused by Atm absence, leading to vigorous growth and rampant genome instability. Senescing Atm-/- cells exhibited ongoing DNA damage and increased amounts of micronuclei. However, their average telomere length did not differ significantly from that of WT cells, suggesting that telomere shortening was not a major factor in their premature senescence. Micronuclei usually herald cytosolic double-stranded DNA fragments – activators of the cGAS-STING pathway. Indeed, continuous presence of a chemical cGAS inhibitor (cGASi) allowed Atm-deficient fibroblasts to evade senescence. Notably, subsequent removal of cGASi did not lead to the expected onset of senescence, suggesting that evasion of senescence at early passage levels leads to loss of this central phenotypic hallmark of Atm-/- fibroblasts and possibly to their immortalization. Remarkably, transcriptomic analysis showed in senescing Atm-/- cells widespread activation of interferon-like responses without activation of the interferon genes themselves, similarly to what we observed in human A-T fibroblasts (M. Haj et al., this meeting). Collectively, these results suggest that a non-canonical pathway downstream of cGAS underlies the accelerated senescence of ATM-deficient fibroblasts.