A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling

Daipayan Banerjee, Kurt Langberg, Salar Abbas, Eric Odermatt, Praveen Yerramothu, Martin Volaric, Matthew A. Reidenbach, Kathy J. Krentz, C. Dustin Rubinstein, David L. Brautigan, Tarek Abbas, Bradley D. Gelfand, Jayakrishna Ambati and Nagaraj Kerur ()
Additional contact information
Daipayan Banerjee: Aravind Medical Research Foundation
Kurt Langberg: University of Virginia School of Medicine
Salar Abbas: University of Virginia School of Medicine
Eric Odermatt: University of Virginia School of Medicine
Praveen Yerramothu: University of Virginia School of Medicine
Martin Volaric: University of Virginia
Matthew A. Reidenbach: University of Virginia
Kathy J. Krentz: University of Wisconsin Biotechnology Center
C. Dustin Rubinstein: University of Wisconsin Biotechnology Center
David L. Brautigan: University of Virginia School of Medicine
Tarek Abbas: University of Virginia
Bradley D. Gelfand: University of Virginia School of Medicine
Jayakrishna Ambati: University of Virginia School of Medicine
Nagaraj Kerur: University of Virginia School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-24

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26240-9

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