Cited by 1,101interferon and immune responsesPhosphodiesterase function and regulationDNA and Nucleic Acid Chemistry

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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.

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Gao, Pu, Ascano, Manuel, Wu, Yang, Barchet, Winfried, Gaffney, Barbara L., Zillinger, Thomas, Serganov, Artem A., Liu, Yizhou, Jones, Roger A., Hartmann, Gunther, Tuschl, Thomas, Patel, Dinshaw J.·2013·Cell

DOI 10.1016/j.cell.2013.04.046PMC PMC4382009

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Abstract

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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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: Gao, Pu
Ascano, Manuel
Barchet, Winfried
Zillinger, Thomas
Liu, Yizhou
Jones, Roger A.
Hartmann, Gunther
Tuschl, Thomas
Patel, Dinshaw J.
Venue: Cell
Publisher: Elsevier BV
Published: 2013-05
Volume: 153
Issue: 5
Pages: 1094-1107
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2013.04.046
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 387 d)
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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Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase.

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