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Bloom syndrome protein restrains innate immune sensing of DNA damage by cGAS.

ABSTRACT: Cellular innate immune sensors of DNA are essential for host defense against invading pathogens. However, the presence of self-derived DNA inside cells poses a biological risk of triggering an inappropriate immune response. The mechanisms limiting induction of inflammation by self nucleic acids are poorly understood. BLM RecQ like helicase is essential for the maintenance of genome integrity and deficient in Bloom syndrome, a rare genetic disease characterized by genome instability, susceptibility to cancer and immunodeficiency. Here, we show that BLM-deficient cells exhibit a constitutively upregulated inflammatory interferon-stimulated gene (ISG) signature. Restoring BLM expression reverts ISG expression to baseline. ISG expression in BLM-deficient fibroblasts is mediated by the cGAS-STING-IRF3 cytosolic DNA sensing pathway. Increased DNA damage or downregulation of the cytoplasmic exonuclease TREX1 enhances ISG expression in BS fibroblasts, and cytoplasmic micronuclei positive for cGAS are increased in BLM-deficient fibroblasts. Finally, BS patients demonstrate elevated ISG expression in peripheral blood. We conclude that BLM is essential to limit the expression of pro-inflammatory genes resulting from the sensing of DNA damage products by the cGAS-STING-IRF3 pathway. These results reveal an unexpected role for BLM in limiting ISG induction, thus connecting DNA damage to innate immunity, which may contribute to human pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123447 | GEO | 2019/03/26

REPOSITORIES: GEO

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Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

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The noncanonical cGAS-STING-PERK pathway enables a selective translation program and underlies organ fibrosis [STING2]

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2021-09-09 | PXD019359 | Pride

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IRF3 and type I interferons fuel a fatal response to myocardial infarction [bulk RNA-Seq]

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cGAS Senses Translation Stress Through Direct Binding to Ribosomes

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