Overview
- The Science study identifies unrepaired DNA‑protein crosslinks as upstream triggers of a chronic inflammatory program that drives degenerative aging phenotypes.
- Researchers show that the SPRTN protease repairs these crosslinks during DNA replication and mitosis, expanding its known role in genome maintenance.
- In cell systems, SPRTN loss led to persistent crosslinks, chromosome segregation errors, micronuclei, and cytosolic DNA that activated the cGAS‑STING pathway.
- A mouse model carrying an RJALS‑associated SPRTN mutation exhibited accumulated crosslinks, strong interferon responses, reduced body size, craniofacial and eye defects, and premature hair graying, with some abnormalities originating in embryogenesis.
- Genetic or pharmacologic cGAS‑STING inhibition from early development prevented developmental lethality and lessened premature‑aging traits, though rescue was incomplete and remains a preclinical finding.