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J Exp Med. 2018 May 7;215(5):1287-1299. doi: 10.1084/jem.20180139. Epub 2018 Apr 5.

The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer.

Li T1,2, Chen ZJ3,2,4.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX tuo.li@utsouthwestern.edu.
2
Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX.
3
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX zhijian.chen@utsouthwestern.edu.
4
Howard Hughes Medical Institute, Chevy Chase, MD.

Abstract

Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING. However, cGAS can be activated by double-stranded DNA irrespective of the sequence, including self-DNA. Although how cGAS is normally kept inactive in cells is still not well understood, recent research has provided strong evidence that genomic DNA damage leads to cGAS activation to stimulate inflammatory responses. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer.

PMID:
29622565
PMCID:
PMC5940270
DOI:
10.1084/jem.20180139
[Indexed for MEDLINE]
Free PMC Article

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