RNase H2 catalytic core Aicardi-Goutières syndrome–related mutant invokes cGAS–STING innate immune-sensing pathway in mice

Pokatayev, Vladislav; Hasin, Naushaba; Chon, Hyongi; Cerritelli, Susana M.; Sakhuja, Kiran; Ward, Jerrold M.; Morris, H. Douglas; Yan, Nan; Crouch, Robert J.

doi:10.1084/jem.20151464

Cited by 200 publications

(174 citation statements)

References 32 publications

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“…Further findings suggest the possibility that release of MUS81-induced cytosolic DNA by prostate cancer cells contributes to STING activation (Ho et al 2016), where such fragments might be a by-product of MUS81-mediated replication fork processing in these cells (Ciccia et al 2008). Moreover, RNase H2 deficiency, the most frequent cause of the autoinflammatory disease Aicardi-Goutières syndrome (AGS), triggers cGAS/STING activation (Crow and Manel 2015;Mackenzie et al 2016;Pokatayev et al 2016). It is possible that dsDNA fragments accumulate in this setting as a byproduct of repair reactions associated with strand breaks that could be triggered by conflicts between DNA replication and transcription due to the accumulation of genomic RNA-DNA hybrids (R loops) in RNase H2-deficient cells or to defective ribonucleic acid excision repair leading to persistent genomic DNA strand breaks (Mackenzie et al 2016).…”

Section: Discussionmentioning

confidence: 99%

A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1

et al. 2017

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Radiotherapy and chemotherapy are effective treatment methods for many types of cancer, but resistance is common. Recent findings indicate that antiviral type I interferon (IFN) signaling is induced by these treatments. However, the underlying mechanisms still need to be elucidated. Expression of a set of IFN-stimulated genes comprises an IFN-related DNA damage resistance signature (IRDS), which correlates strongly with resistance to radiotherapy and chemotherapy across different tumors. Classically, during viral infection, the presence of foreign DNA in the cytoplasm of host cells can initiate type I IFN signaling. Here, we demonstrate that DNA-damaging modalities used during cancer therapy lead to the release of ssDNA fragments from the cell nucleus into the cytosol, engaging this innate immune response. We found that the factors that control DNA end resection during doublestrand break repair, including the Bloom syndrome (BLM) helicase and exonuclease 1 (EXO1), play a major role in generating these DNA fragments and that the cytoplasmic 3 ′ -5 ′ exonuclease Trex1 is required for their degradation. Analysis of mRNA expression profiles in breast tumors demonstrates that those with lower Trex1 and higher BLM and EXO1 expression levels are associated with poor prognosis. Targeting BLM and EXO1 could therefore represent a novel approach for circumventing the IRDS produced in response to cancer therapeutics.

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Section: Discussionmentioning

confidence: 99%

A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1

et al. 2017

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“…Indeed, induction of IFN-I responses in the absence of discernible microbial infection, a process called ‘sterile inflammation,’ was initially described in the context of rare human monogenic diseases of auto-inflammation [25 • ]. Regarding cytosolic DNA sensing, loss-of-function mutations in the cytoplasmic DNA endonuclease TREX1 [26,27 •• ,28,29], or ribonuclease RNase H2 [30–33,34 •• ] directly drive cGAS–STING pathway activation by self-DNA, precipitating a multi-organ inflammatory disease called Aicardi–Goutieres Syndrome (AGS). In TREX1-deficient cells, retroviral DNA elements from the cellular genome spontaneously accumulate in the cytoplasm [27 •• ], whereas deficiency of RNase H2 precipitates genomic instability [32,33,34 •• ].…”

Section: Dna Sensing During Inflammationmentioning

confidence: 99%

“…Recently, five independent studies have shed new insight into the role of the cGAS–STING axis in maintenance of genomic integrity by intrinsic sensing of genotoxic stress [34 •• ,59 •• ,60 •• ,61 •• ,62 •• ]. In cells deficient in ribonuclease RNase H2, a causative factor in inflammatory AGS that is involved in DNA synthesis and repair [30–33,34 •• ], cGAS specifically localizes to micronuclei, which are formed from mis-segregation of chromosomal DNA, where it initiates an inflammatory response [34 •• ]. Similarly, continuous passaging of cells [59 •• ,60 •• ], hyperoxic conditions [60 •• ] or ionizing radiation [61 •• ,62 •• ] also activate cGAS-mediated sensing of damaged genomic DNA fragments or micronuclei, with the resulting inflammatory response driving cellular senescence.…”

Section: Cancer Cancer Therapy and Genotoxic Stressmentioning

confidence: 99%

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

Dhanwani

Takahashi

Sharma

2018

Current Opinion in Immunology

100

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In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2′–5′-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS–STING–IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults.

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“…A point mutation in RNase H2A (G37S) causes catalytic disability and accumulated RNA/DNA hybrids, followed by increased expression of ISG genes. STING deficiency partially rescues the phenomenon caused by RNase H2A mutation (Pokatayev et al, 2016). …”

Section: Innate Immune Responses Induced By Dna Sensorsmentioning

confidence: 99%

DNA sensor cGAS-mediated immune recognition

et al. 2016

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The host takes use of pattern recognition receptors (PRRs) to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFκB or TBK1-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types. cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from adenosine triphosphate and guanosine triphosphate. cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon production. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

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RNase H2 catalytic core Aicardi-Goutières syndrome–related mutant invokes cGAS–STING innate immune-sensing pathway in mice

Abstract: Mice with a mutated form of RNase H2 found in patients with the neuroinflammatory Aicardi-Goutières Syndrome develop a lethal, cGAS–STING–dependent disease.

Cited by 200 publications

References 32 publications

A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1

A prosurvival DNA damage-induced cytoplasmic interferon response is mediated by end resection factors and is limited by Trex1

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

DNA sensor cGAS-mediated immune recognition

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