New joint publication by the Dikic and Beli labs on how DNA-protein cross-links promote cGAS-STING–driven premature aging and embryonic lethality
Tomaskovic I, Prieto-Garcia C, Boskovic M, Glumac M, Tsai TL, Mosler T, Kazi R, Rathore R, Andrade J, Hoffmann M, Giuliani G, Jacomin AC, Pereira RS, Knop E, Wachsmuth L, Beli P, Husnjak K, Pasparakis M, Ablasser A, Krause DS, Potente M, Papathanasiou S, Terzic J, Dikic I (2026) DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.Science, 391(6784):eadx9445 Link
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 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.
Read the full paper here: https://www.science.org/doi/10.1126/science.adx9445
