Interferon Stimulatory DNA activates the DNA damage signaling through ATM and DNA-PK sensing

In eukaryotic cells, DNA is normally confined in the nucleus and mitochondria and the presence of DNA in the cytoplasm is a danger signal that activates innate immune responses.Upon detection of cytoplasmic dsDNA in mammalian cells, the cGAS-STING pathway induces type I-Interferon (IFN-I) and inflammatory responses, a key step in innate immune activation.Since its discovery, Interferon Stimulatory DNA (ISD), a linear double-stranded DNA, has been largely used to study the cGAS-STING pathway and its regulation.Here, we show that ISD also stimulates DNA damage signaling.We show that ISD activates both ATM and DNA-PK, the sensor kinases of the DNA damage response, independently of cGAS-STING signaling.Our results demonstrate that the DNA damage response, which is usually considered a response to genomic DNA lesions, can be promoted by foreign DNA.Our data further suggest that ISDs coordinate two central protective functions of cells, the innate immunity and DNA damage checkpoints.