DNA-protein cross-links promote cGAS-STING–driven premature aging and embryonic lethality
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 <i>Sprtn</i> 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.
Authors
- Daniela S. Krause (ORCID: https://orcid.org/0000-0003-3603-1119)
- Petra Beli (ORCID: https://orcid.org/0000-0001-9507-9820)
- Jorge Andrade (ORCID: https://orcid.org/0000-0002-4577-8620)
- Thorsten Mosler (ORCID: https://orcid.org/0000-0003-1800-2680)
- Koraljka Husnjak (ORCID: https://orcid.org/0000-0003-0573-6239)
- Raquel Pereira (ORCID: https://orcid.org/0000-0002-9863-6538)
- Mateo Glumac (ORCID: https://orcid.org/0000-0001-5597-7431)
- Rubina Kazi
- Anne‐Claire Jacomin (ORCID: https://orcid.org/0000-0001-8761-1514)
- Michael Potente (ORCID: https://orcid.org/0000-0002-5689-0036)
- M. Hoffmann (ORCID: https://orcid.org/0009-0008-5061-2722)
- Andrea Ablasser (ORCID: https://orcid.org/0000-0002-8475-8999)
- Maria Bošković (ORCID: https://orcid.org/0000-0001-7701-0643)
- Manolis Pasparakis (ORCID: https://orcid.org/0000-0002-9870-0966)
- Ines Tomašković
- Cristian Prieto‐Garcia (ORCID: https://orcid.org/0000-0002-7576-1061)
- Giulio Giuliani (ORCID: https://orcid.org/0000-0002-4648-0076)
- Laurens Wachsmuth (ORCID: https://orcid.org/0000-0003-1701-9384)
- Stamatis Papathanasiou (ORCID: https://orcid.org/0000-0001-6969-044X)
- Tsung-Lin Tsai
- Elias Knop
- Janos Terzic
- Ivan Dikic
- Rajeshwari Rathore
Institutions
- Goethe University Frankfurt (DE)
- German Cancer Research Center (DE)
- University of Cologne (DE)
- Johannes Gutenberg University Mainz (DE)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Georg Speyer Haus (DE)
- Institute of Molecular Biology (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Split (HR)
Publication Details
- Journal
- Science
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1126/science.adx9445
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00