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

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

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

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Item Type:	Article
Title:	DNA-protein cross-links promote cGAS-STING–driven premature aging and embryonic lethality
Creators Name:	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 and Dikic, Ivan
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.
Keywords:	Animal Disease Models, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, DNA, DNA Damage, DNA Replication, Embryo Loss, Gene Knock-In Techniques, Innate Immunity, Membrane Proteins, Metalloendopeptidases, Nucleotidyltransferases, Premature Aging, Progeria, STING Protein, Signal Transduction, cGAS-STING Signaling Pathway, Animals, Mice
Source:	Science
ISSN:	0036-8075
Publisher:	American Association for the Advancement of Science
Volume:	391
Number:	6784
Page Range:	eadx9445
Date:	29 January 2026
Official Publication:	https://doi.org/10.1126/science.adx9445
PubMed:	View item in PubMed
Related to:	URL URL Type https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE268005 External Dataset https://proteomecentral.proteomexchange.org/?pxid=PXD051378 External Dataset https://proteomecentral.proteomexchange.org/?pxid=PXD067624 External Dataset

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