Cyclic oligoadenylate signaling by type III CRISPR systems. Multisubunit type III CRISPR-Cas complexes (denoted Csm or Cmr) detect foreign RNA and carry out nucleic acid cleavage directly and by recruiting CRISPR ancillary enzymes. RNA bound by the CRISPR-Cas complex, as a result of complementary base-pairing with the crRNA, is degraded by the Cas7 (Csm3/Cmr4) backbone subunits (Benda et al. 2014; Ramia et al. 2014; Staals et al. 2014; Tamulaitis et al. 2014). Bona fide RNA targets contain a 3′-region that is not complementary to the 8 nt 5′-end of the crRNA, which allosterically activates the Cas10 subunit to synthesize cyclic oligoadenylates (cOA) and cleave ssDNA (Kazlauskiene et al. 2017; Niewoehner et al. 2017). Target RNA cleavage by Cas7 subunits switches off both the ssDNase and cOA synthesis activities of Cas10 (Rouillon et al. 2018). cOA can activate Csx1/Csm6 ribonucleases that cleave RNA nonspecifically, DNases such as NucC (Lau et al. 2020) and the CRISPR ancillary nuclease 1 (Can1) (McMahon et al. 2020), and the related dual-specificity cOA-activated RNase and DNase (Card1)/Can2 (Rostøl et al. 2021; Zhu et al. 2021), which help eliminate invading mobile genetic elements (MGE). cOA can also stimulate the transcription regulator Csa3, which alters CRISPR loci and cas gene expression to promote MGE elimination (Lawrence et al. 2020).
