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Review
. 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

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Free PMC article
Review

The cGAS-cGAMP-STING Pathway Connects DNA Damage to Inflammation, Senescence, and Cancer

Tuo Li et al. J Exp Med. .
Free PMC article

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.

Figures

Figure 1.
Figure 1.
Inflammatory response is another biological outcome of genomic instability. Genotoxic stress leads to DNA damage repair, cellular senescence, and cell death in a manner that depends on the severity of the DNA damage. The cGAS–cGAMP–STING pathway is activated by DNA damage to mediate antitumor immunity, senescence, and inflammatory responses.
Figure 2.
Figure 2.
The cGAS–cGAMP–STING pathway detects cytoplasmic DNA after DNA damage and activate type I IFNs and other cytokines. Like DDR, the immune response is induced by various forms of genotoxic stress, ranging from ionizing radiation, DNA-damaging drugs, oxidative stress, oncogenic signaling, telomere shortening, and chromosome missegregation to viral infections and activation of endogenous retroelements. Nuclear DNA damage can generate cytoplasmic DNA in two possible ways. First, certain genomic damage causes chromosome to missegregate in subsequent cell division; the chromosome failing to partition into the new nuclei will form micronuclei. When the nuclear evelope (NE) of micronuclei ruptures, the DNA content is exposed to cGAS surveillance. Second, nuclear DNA damage can also generate ssDNA in the cytoplasm in a less understood process (dashed line and question mark). Such cytoplasmic DNA is degraded by Trex1, the loss of which leads to cGAS activation. Active cGAS dimerizes to synthesize cGAMP from GTP and ATP. cGAMP acts as a second messenger to activate STING on the ER surface. STING then activates transcription factors IRF3 and NF-κB via kinases TBK1 and IKK, respectively. IRF3 and NF-κB translocate into the nucleus to elicit the expression of IFNs and other cytokines. Damage to mitochondria or mitochondrial DNA can also lead to accumulation of mitochondrial DNA in the cytosol, resulting in cGAS activation and sterile inflammation (not depicted).

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