Journal Article

DKFZ-2026-00246

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.

Tomaskovic, I. ; Prieto-Garcia, C. ; Boskovic, M. ; Glumac, M. ; Tsai, T.-L. ; Mosler, T. ; Kazi, R. ; Rathore, R. ; Andrade, J. ; Hoffmann, M. ; Giuliani, G. ; Jacomin, A.-C. ; Pereira, R. S. ; Knop, E. ; Wachsmuth, L. ; Beli, P. ; Husnjak, K. ; Pasparakis, M. ; Ablasser, A. ; Krause, D. S.DKFZ* ; Potente, M. ; Papathanasiou, S. ; Terzic, J. ; Dikic, I.

2026
Assoc. Washington, DC

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.

Keyword(s): Animals (MeSH) ; Nucleotidyltransferases: metabolism (MeSH) ; Nucleotidyltransferases: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Mice (MeSH) ; DNA Damage (MeSH) ; Aging, Premature: genetics (MeSH) ; Immunity, Innate (MeSH) ; Signal Transduction (MeSH) ; Progeria: genetics (MeSH) ; Progeria: immunology (MeSH) ; DNA: metabolism (MeSH) ; Gene Knock-In Techniques (MeSH) ; Embryo Loss: genetics (MeSH) ; Metalloendopeptidases: genetics (MeSH) ; Metalloendopeptidases: metabolism (MeSH) ; Humans (MeSH) ; DNA Replication (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; STING Protein (MeSH) ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase (MeSH) ; Nucleotidyltransferases ; Membrane Proteins ; Sting1 protein, mouse ; cGAS protein, mouse ; DNA ; Metalloendopeptidases ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase

Note: #DKTKZFB26#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 50 ; Index Chemicus ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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