Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance

Zhou, Wen; Whiteley, Aaron T.; Mann, Carina C. de Oliveira; Morehouse, B.R.; Nowak, Radosław P.; Fischer, Eric S.; Gray, Nathanael S.; Mekalanos, John J.; Kranzusch, Philip J.

doi:10.1016/j.cell.2018.06.026

Cited by 275 publications

(334 citation statements)

References 56 publications

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“…More specifically, dsRNA binding organizes the three conserved aspartic acids in the active site for coordinating the magnesium ions required for catalysis (99). The mechanism by which OASes couple dsRNA binding to 2-5A n synthesis is similar to that of cGAS (Figure 3a), a cytosolic DNA sensor that catalyzes synthesis of 2 ′ −3 ′ cGAMP upon dsDNA binding (101,102). This suggests a conserved mechanism for double-stranded nucleic acid recognition and antiviral signaling.…”

Section: Oligoadenylate Synthases and Rnase Lmentioning

confidence: 94%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

293

286

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Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms. KeywordsdsRNA; RIG-I-like receptor; protein kinase R; oligoadenylate synthase; dsRNA-dependent adenosine deaminase; RNA interference HHS Public Access

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Section: Oligoadenylate Synthases and Rnase Lmentioning

confidence: 94%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

293

286

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“…Crystal structure image of hcGAS-DNA complex was created with NGL Viewer from RCSB Protein Data Bank with accession numbers 6CTA (Rose et al, 2018;Zhou et al, 2018).…”

Section: Foki Induced Double-strand Break Systemmentioning

confidence: 99%

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

et al. 2019

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DNA repair via homologous recombination (HR) is indispensable for genome integrity and cell survival but if unrestrained can result in undesired chromosomal rearrangements. The regulatory mechanisms of HR are not fully understood. Cyclic GMP‐AMP synthase (cGAS) is best known as a cytosolic innate immune sensor critical for the outcome of infections, inflammatory diseases, and cancer. Here, we report that cGAS is primarily a chromatin‐bound protein that inhibits DNA repair by HR, thereby accelerating genome destabilization, micronucleus generation, and cell death under conditions of genomic stress. This function is independent of the canonical STING‐dependent innate immune activation and is physiologically relevant for irradiation‐induced depletion of bone marrow cells in mice. Mechanistically, we demonstrate that inhibition of HR repair by cGAS is linked to its ability to self‐oligomerize, causing compaction of bound template dsDNA into a higher‐ordered state less amenable to strand invasion by RAD51‐coated ssDNA filaments. This previously unknown role of cGAS has implications for understanding its involvement in genome instability‐associated disorders including cancer.

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“…Although CD-NTase activity requires a single monomeric active site, an emerging regulatory feature is the role of enzyme oligomerization. The minimally active cGAS-DNA complex is a 2:2 unit where two molecules of cGAS embrace two molecules of double-stranded DNA [27,28,29 ]. Recent results highlight the role of further higher-order complex formation in cGAS regulation where DNA 'laddering' and a liquid-liquid phase separation process are required for robust enzyme activation [38 ,39 ].…”

Section: Structural Anatomy Of Cd-ntase Enzymesmentioning

confidence: 99%

cGAS and CD-NTase enzymes: structure, mechanism, and evolution

Kranzusch

2019

Current Opinion in Structural Biology

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Cyclic GMP-AMP synthase (cGAS) is a signaling enzyme in human cells that controls immune-sensing of cytosolic DNA. The recent discoveries of diverse structural homologs of cGAS in animals and bacteria reveal that cGAS-like signaling is surprisingly ancient and widespread in biology. Together with the Vibrio cholerae protein dinucleotide cyclase in Vibrio (DncV), cGAS and DncV homologs comprise a family of cGAS/ DncV-like nucleotidyltransferase (CD-NTase) enzymes that synthesize noncanonical RNA signals including cyclic dinucleotides, cyclic trinucleotides, and linear oligonucleotides. Structural and biochemical breakthroughs provide a framework to understand how CD-NTase signaling allows cells to respond to changing environmental conditions. The CD-NTase family also includes uncharacterized human genes like MB21D2 and Mab21L1, highlighting emerging functions of cGAS-like signaling beyond innate immunity.

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Structure of the Human cGAS–DNA Complex Reveals Enhanced Control of Immune Surveillance

Cited by 275 publications

References 56 publications

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

cGAS and CD-NTase enzymes: structure, mechanism, and evolution

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