sTelomere replication stress-induced DNA damage response triggers inflammatory signaling via canonical and non-canonical STING pathways

Telomeres are protected by the shelterin complex, but they are also common fragile sites and are particularly susceptible to replicative stress. We found that depletion of telomeric repeat-binding factor 1 (TRF1), a key shelterin component essential for telomere replication, in mouse embryonic fibroblasts (MEFs) activated ATR- and subsequent ATM-dependent DNA damage responses. TRF1 loss increased the formation of micronuclei and cytosolic DNA, leading to ATR-dependent micronuclear rupture and activation of the cGAS/STING pathway. ATM activation enhanced STING K63 modification, thereby boosting the STING/NFκB pathway. Inhibition of ATM or cGAS reduced the expression of the pro-inflammatory cytokine IL6, with combined inhibition further suppressing IL6 levels. Depletion or inhibition of STING alone decreased production of IL6 and IFNβ, with no major reduction by combined ATM and/or cGAS inhibitors. These findings indicate that STING acts epistatically with ATM- and cGAS-mediated inflammatory responses. Overall, the telomere replication stress and dysfunction triggered by loss of TRF1 promotes inflammation through the ATR/cGAS/STING and ATM/STING pathways.