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DNA Repair Inhibition Leads to Active Export of Repetitive Sequences to the Cytoplasm Triggering an Inflammatory Response

ABSTRACT: Cytoplasmic DNA (cytoDNA) is a strong immune stimulus that evolved to protect the cell against invasion byDNA viruses. Curiously, cytoDNA is also found in the absence of viral infection in conditions such as cancer, neurodegeneration and immune system disorders. In mouse microglia, agents that enhance DNA damage lead to the accumulation of cytoDNA. In this report we demonstrate that cytoDNA resulting from reduced DNA repair comes from the cell nucleus and is actively exported to the cytoplasm by a CRM1-dependent mechanism. Once in the cytoplasm, it is degraded either by a cytosolic exonuclease, Trex1, or an autophagy pathway that ends with degradation in the lysosome. Blocking nuclear export, overexpression of Trex1 or induction ofautophagy are each able to block the accumulation of cytoDNA and prevent the emergence of aninflammatory reaction.Genomics analysis confirms that cytoDNA originates in the nuclear genome and not the mitochondria.Moreover, these fragments are enriched intranscriptionally inactive, intergenic regions, in particular repetitive elements and AT-rich sequences. These findings offer new insights into the cellular dynamics that create cytoDNA and thus offer new pathways to blunt its appearance and the downstream inflammatory responses

ORGANISM(S): Mus musculus

PROVIDER: GSE164337 | GEO | 2021/10/04

REPOSITORIES: GEO

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