Abstract
Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), produced by cyclic GMP-AMP synthase (cGAS), stimulates the production of type I interferons (IFN). Here we show that cGAMP activates DNA damage response (DDR) signaling independently of its canonical IFN pathways. Loss of cGAS dampens DDR signaling induced by genotoxic insults. Mechanistically, cGAS activates DDR in a STING-TBK1-dependent manner, wherein TBK1 stimulates the autophosphorylation of the DDR kinase ATM, with the consequent activation of the CHK2-p53-p21 signal transduction pathway and the induction of G1 cell cycle arrest. Despite its stimulatory activity on ATM, cGAMP suppresses homology-directed repair (HDR) through the inhibition of polyADP-ribosylation (PARylation), in which cGAMP reduces cellular levels of NAD+; meanwhile, restoring NAD+ levels abrogates cGAMP-mediated suppression of PARylation and HDR. Finally, we show that cGAMP also activates DDR signaling in invertebrate species lacking IFN (Crassostrea virginica and Nematostella vectensis), suggesting that the genome surveillance mechanism of cGAS predates metazoan interferon-based immunity.
Highlights
Cyclic guanosine monophosphate-adenosine monophosphate, produced by cyclic GMP-AMP synthase, stimulates the production of type I interferons (IFN)
We show that cyclic GMP-AMP synthase (cGAS)-STING signaling promotes DNA damage response (DDR) signaling activity, resulting in the activation of ATM, G1 cell cycle arrest, and impaired DNA repair via homologous recombination
Human monocytic THP1 cells were stimulated with Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and the status of DDR signaling was assessed through monitoring the phosphorylation status of key DDR signaling molecules, including histone H2AX, ATM, and CHK2, by immunoblotting. cGAMP treatment of THP1 cells induced phosphorylation of all these proteins (Fig. 1b and Supplementary Fig. 1a)
Summary
Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), produced by cyclic GMP-AMP synthase (cGAS), stimulates the production of type I interferons (IFN). Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA-sensing PRR that triggers downstream signaling pathways by catalyzing the formation of a second messenger, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). We show that cGAS-STING signaling promotes DDR signaling activity, resulting in the activation of ATM, G1 cell cycle arrest, and impaired DNA repair via homologous recombination. These data illustrate a previously undiscovered, evolutionarily conserved genome surveillance function of the second messenger cGAMP and introduce new insights into cGAS/cGAMP signaling in an array of biological and therapeutic contexts such as cancer, aging, immunity, cancer therapeutics, and genome editing
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