1. Genome Replication Is Associated With Release of Immunogenic DNA Waste.
- Author
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Schubert, Nadja, Schumann, Tina, Daum, Elena, Flade, Karolin, Ge, Yan, Hagedorn, Lara, Edelmann, Winfried, Müller, Luise, Schmitz, Marc, Kuut, Gunnar, Hornung, Veit, Behrendt, Rayk, and Roers, Axel
- Subjects
EXONUCLEASES ,DNA ,DNA replication ,ENDONUCLEASES ,SYSTEMIC lupus erythematosus ,GENOMES ,TYPE I interferons - Abstract
Innate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be caused by defects of the cytosolic DNase 3'repair exonuclease 1 (TREX1). TREX1 loss-of-function alleles are also associated with systemic lupus erythematosus (SLE). Chronic activation of innate antiviral immunity in TREX1-deficient cells depends on the DNA sensor cGAS, implying that accumulating TREX1 DNA substrates cause the inflammatory pathology. Retrotransposon-derived cDNAs were shown to activate cGAS in TREX1-deficient neuronal cells. We addressed other endogenous sources of cGAS ligands in cells lacking TREX1. We find that induced loss of TREX1 in primary cells induces a rapid IFN response that requires ongoing proliferation. The inflammatory phenotype of Trex1
-/- mice was partially rescued by additional knock out of exonuclease 1, a multifunctional enzyme providing 5' flap endonuclease activity for Okazaki fragment processing and postreplicative ribonucleotide excision repair. Our data imply genome replication as a source of DNA waste with pathogenic potential that is efficiently degraded by TREX1. [ABSTRACT FROM AUTHOR]- Published
- 2022
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