DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality

• 成果类型: Article
• 署名作者: Tomaskovic, Ines; Prieto-Garcia, Cristian; Boskovic, Maria; Glumac, Mateo; Tsai, Tsung-Lin; Mosler, Thorsten; Kazi, Rubina; Rathore, Rajeshwari; Andrade, Jorge; Hoffmann, Marina; Giuliani, Giulio; Jacomin, Anne-Claire; Pereira, Raquel S.; Knop, Elias; Wachsmuth, Laurens; Beli, Petra; Husnjak, Koraljka; Pasparakis, Manolis; Ablasser, Andrea; Krause, Daniela S.; Potente, Michael; Papathanasiou, Stamatis; Terzic, Janos; Dikic, Ivan
• 署名单位: Goethe University Frankfurt; Goethe University Frankfurt Hospital; University of Split; Institute of Molecular Biology (IMB); Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Goethe University Frankfurt; Goethe University Frankfurt; University of Cologne; University of Cologne; University of Cologne; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Johannes Gutenberg University of Mainz; Johannes Gutenberg University of Mainz; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adx9445
• 发表日期: 2026-01-29
• 页码: eadx9445
• 关键词: differential expression; peptide identification; topoisomerase-ii; damage; accumulation; SPARTAN; systems; adapter; repair

摘要

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.