Ines Tomašković, Cristian Prieto‐Garcia, Maria Bošković, Mateo Glumac, Tsung-Lin Tsai, Thorsten Mosler, Rubina Kazi, Rajeshwari Rathore, Jorge Andrade, Marina Hoffmann, Giulio Giuliani, Anne‐Claire Jacomin, Raquel Pereira, Elias Knop, Laurens Wachsmuth, Petra Beli, Koraljka Husnjak, Manolis Pasparakis, Andrea Ablasser, Daniela S. Krause, Michael Potente, Stamatis Papathanasiou, Janos Terzic, Ivan Dikic
DNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes.