Stimulator of interferon genes (STING) plays a central role in sensing intracellular DNA in mammalian cells. By studying the ability of adenoviral oncoprotein E1A to repress DNA sensing in human cells, Burleigh et al. have found a STING-independent intracellular DNA sensing pathway that relies on DNA-dependent protein kinase (DNA-PK). They report that DNA-PK–dependent DNA sensing pathway is not activated by cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), a cyclic dinucleotide synthesized that is sensed by STING. Furthermore, DNA-PK–dependent DNA sensing is intact in STING-deficient cells. In-depth molecular characterization of this pathway is needed to understand how DNA-PK and STING-dependent DNA sensing pathways function in tandem to sense and respond to intracellular DNA.
