Fig. 1
cGAS/STING activation by radiation-induced DNA damage. a Cytosolic dsDNA migrates in micronuclei or directly in the cytosol and is recognized by cGAS which catalyzes cGAMP synthesis after dsDNA binding. cGAMP binds to STING, which translocates from the ER to the Golgi, recruits IKK and TBK1 and activates IRF3 and IкBα, resulting in release of NF-кB. IRF3 and NF-кB translocate into the nucleus and induce transcription of IFN type I and other proinflammatory chemokines. IFN binds to IFNAR1/2 receptors, activates JAK, and STAT1/2 is phosphorylated. The heterodimer translocates to the nucleus and induces expression of ISGs. b Activation of DDR kinases ATR, WEE1, ATM, and DNA-PK PARP1 after IR induces DNA repair. Accumulation of cytosolic dsDNA and formation of micronuclei leads to activation of overall cGAS/STING metabolism. ATR activation affects PD-L1 surface expression via CHK1 and STAT1/3-IRF1 signaling. ATM ataxia-telangiectasia mutated protein, ATR ataxia-telangiectasia and Rad3-related protein, cGAMP cyclic GMP-AMP, cGAS cyclic GMP-AMP synthase, CHK1 checkpoint kinase 1, DDR DNA damage response, DNA-PK DNA-dependent protein kinase, ER endoplasmic reticulum, IFN interferon, IFNAR1/2 interferon receptor 1/2, IKK IκB kinases, IRF1/3 interferon regulatory factor 1/3, ISG interferon-stimulated gene, JAK Janus kinase, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, PARP1 poly-ADP-ribose polymerase 1, PD-L1 programmed death ligand 1, STAT1/2/3 signal transducer and activator of transcription 1/2/3, STING stimulator of interferon genes, TBK1 TANK binding kinase 1; Wee1 Wee1 G2 checkpoint kinase. Adapted from “Blank Pathway (Linear),” by BioRender.com (2023)