Peer-reviewed veterinary case report
DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
- Journal:
- Science (New York, N.Y.)
- Year:
- 2026
- Authors:
- Tomaskovic, Ines et al.
- Affiliation:
- Institute of Biochemistry II · Germany
- Species:
- rodent
Abstract
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 aknock-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.
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Search related cases →Original publication: https://pubmed.ncbi.nlm.nih.gov/41610251/