TY  - JOUR
AU  - Tomaskovic, Ines
AU  - Prieto-Garcia, Cristian
AU  - Boskovic, Maria
AU  - Glumac, Mateo
AU  - Tsai, Tsung-Lin
AU  - Mosler, Thorsten
AU  - Kazi, Rubina
AU  - Rathore, Rajeshwari
AU  - Andrade, Jorge
AU  - Hoffmann, Marina
AU  - Giuliani, Giulio
AU  - Jacomin, Anne-Claire
AU  - Pereira, Raquel S
AU  - Knop, Elias
AU  - Wachsmuth, Laurens
AU  - Beli, Petra
AU  - Husnjak, Koraljka
AU  - Pasparakis, Manolis
AU  - Ablasser, Andrea
AU  - Krause, Daniela S
AU  - Potente, Michael
AU  - Papathanasiou, Stamatis
AU  - Terzic, Janos
AU  - Dikic, Ivan
TI  - DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
JO  - Science / Science now
VL  - 391
IS  - 6784
SN  - 0036-8075
CY  - Washington, DC
PB  - Assoc.
M1  - DKFZ-2026-00246
SP  - eadx9445
PY  - 2026
N1  - #DKTKZFB26#
AB  - 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.
KW  - Animals
KW  - Nucleotidyltransferases: metabolism
KW  - Nucleotidyltransferases: genetics
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Mice
KW  - DNA Damage
KW  - Aging, Premature: genetics
KW  - Immunity, Innate
KW  - Signal Transduction
KW  - Progeria: genetics
KW  - Progeria: immunology
KW  - DNA: metabolism
KW  - Gene Knock-In Techniques
KW  - Embryo Loss: genetics
KW  - Metalloendopeptidases: genetics
KW  - Metalloendopeptidases: metabolism
KW  - Humans
KW  - DNA Replication
KW  - Disease Models, Animal
KW  - Female
KW  - STING Protein
KW  - Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
KW  - Nucleotidyltransferases (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Sting1 protein, mouse (NLM Chemicals)
KW  - cGAS protein, mouse (NLM Chemicals)
KW  - DNA (NLM Chemicals)
KW  - Metalloendopeptidases (NLM Chemicals)
KW  - STING Protein (NLM Chemicals)
KW  - Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41610251
DO  - DOI:10.1126/science.adx9445
UR  - https://inrepo02.dkfz.de/record/308934
ER  -