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Science 339 (6121): 763-764

Copyright © 2013 by the American Association for the Advancement of Science

Sensing the Dark Side of DNA

Luke A. J. O'Neill

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland.

Figure 1
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DNA sensor. (A) A well-characterized signaling pathway involves adenylate cyclase, which is activated by many hormones via G protein–coupled receptors (GPCRs) at the cell surface. Adenylate cyclase produces the second messenger molecule cAMP, which activates protein kinase A (PKA) and many cellular processes. (B) DNA from diverse microbes is sensed in the cytosol of infected cells as a danger signal. The cyclase cGAS binds this DNA, becomes catalytically active, and generates cGAMP as a second messenger. cGAMP binds to STING, which activates two signaling pathways that increase the expression of immune and inflammatory genes, thereby promoting host defense. The same process is likely to sense host DNA that leaks out of mitochondria or the nucleus in damaged cells, acting as a danger signal. Certain microbes make c-di-GMP or c-di-AMP, which activate STING; other microbes (and protozoa) can also synthesize cGAMP. How other DNA sensors fit into this process is unclear.



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