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Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase.
Open accessAbstract
Recent studies identified cyclic GMP-AMP (cGAMP) as a metazoan second messenger triggering an interferon response. cGAMP is generated from GTP and ATP by cytoplasmic dsDNA sensor cGAMP synthase (cGAS). We combined structural, chemical, biochemical, and cellular assays to demonstrate that this second messenger contains G(2',5')pA and A(3',5')pG phosphodiester linkages, designated c[G(2',5')pA(3',5')p]. We show that, upon dsDNA binding, cGAS is activated through conformational transitions, resulting in formation of a catalytically competent and accessible nucleotide-binding pocket for generation of c[G(2',5')pA(3',5')p]. We demonstrate that cyclization occurs in a stepwise manner through initial generation of 5'-pppG(2',5')pA prior to cyclization to c[G(2',5')pA(3',5')p], with the latter positioned precisely in the catalytic pocket. Mutants of cGAS dsDNA-binding or catalytic pocket residues exhibit reduced or abrogated activity. Our studies have identified c[G(2',5')pA(3',5')p] as a founding member of a family of metazoan 2',5'-containing cyclic heterodinucleotide second messengers distinct from bacterial 3',5' cyclic dinucleotides.
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“In the presence of ATP and GTP, cGAS catalyzes the production of 2′3′ cyclic GMP-AMP (cGAMP) which stimulates the adaptor protein, STING.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Gao et al., 2013
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In the citing paper
“Cytosolic dsDNA binds to cGAS, catalyzing the generation of cyclic GMP-AMP (cGAMP).”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [257]
In the citing paper
“cGAS a 522 amino acid protein, is a cytosolic DNA sensor that activates innate immunity upon sensing aberrant double stranded (ds) DNA molecules irrespective of the source.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Gao et al., 2013
In the citing paper
“STING recruits TANK-binding kinase 1 (TBK1) and IK-B kinase (IKK) (Ablasser et al., 2013; Diner et al., 2013; Gao et al., 2013; Sun et al., 2013, 2018; Wu et al., 2013; Zhang et al., 2013; Ablasser and Gulen, 2016; Chen et al., 2016).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Gao et al., 2013
In the citing paper
“cGAS-STING pathway is a cytosolic DNA sensing signaling.”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [257]
In the citing paper
“Then, STING recruits and phosphorylates TBK1, which further activates downstream IRF3 and upregulates IFN-I [257–259].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [257]
In the citing paper
“Stimulated by cGAMP, STING changes from monomer to dimer and translocates from ER to perinuclear microsome.”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [257]
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Metadata
- Authors
- Gao, P., Ascano, M., Wu, Y., Barchet, W., Gaffney, B. L., Zillinger, T., Serganov, A. A., Liu, Y., Jones, R. A., Hartmann, G., Tuschl, T., & Patel, D. J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- University of Bonn (DE)
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Tuschl, Thomas
- Patel, Dinshaw J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 153
- Issue
- 5
- Pages
- 1094-1107
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4382009
- OpenAlex
- W2123645680
- Cited by
- 1,101
- References
- 43
- Citations by year
- 2026: 95 · 2025: 122 · 2024: 118 · 2023: 106 · 2022: 112 · 2021: 105 · 2020: 92 · 2019: 76 · 2018: 43 · 2017: 59 · 2016: 48 · 2015: 47 · 2014: 45 · 2013: 33
- FWCI
- 31.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- National Institute of General Medical Sciences (R01GM079760, GM79760)
- Argonne National Laboratory
- Brookhaven National Laboratory
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- cyclic GMP-AMP, cGAMP, cGAS, interferon response, conformational activation, catalytic pocket, nucleotide-binding pocket
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Adenosine Triphosphate, Amino Acid Sequence, Animals, DNA, Guanosine Triphosphate, Humans, Models, Chemical, Models, Molecular, Molecular Sequence Data, Nucleotides, Cyclic, Nucleotidyltransferases, 2',5'-Oligoadenylate Synthetase, Dinucleoside Phosphates, Second Messenger Systems, Sequence Alignment, Crystallography, X-Ray, Mice
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