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

• Published in: The Journal of experimental medicine Vol. 215; no. 5; pp. 1287 - 1299
• Main Authors: Li, Tuo, Chen, Zhijian J.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 07.05.2018
• Subjects: Activation; Adenosine monophosphate; AMP; Cancer; Cyclic GMP; Damage detection; Deoxyribonucleic acid; DNA; DNA damage; Genomic instability; Guanosine; Immune response; Immune system; Inflammation; Innate immunity; Microorganisms; Nucleotide sequence; Reviews; Senescence; Stability
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20180139

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.