Discovery of Oligonucleotide Signaling Mediated by CRISPR-Associated Polymerases Solves Two Puzzles but Leaves an Enigma

The signature component of type III CRISPR-Cas systems is the Cas10 protein that consists of two Palm domains homologous to those of DNA and RNA polymerases and nucleotide cyclases and an HD nuclease domain. However, until very recently, the activity of the Palm domains and their role in CRISPR function have not been experimentally established. Most of the type III CRISPR-Cas systems and some type I systems also encompass proteins containing the CARF (CRISPR-associated Rossmann fold) domain that has been predicted to regulate CRISPR functions via nucleotide binding, but its function in CRISPR-Cas remained obscure. Two independent recent studies show that the Palm domain of Cas10 catalyzes synthesis of oligoadenylates, which bind the CARF domain of the Csm6 protein and activate its RNase domain that cleaves foreign transcripts enabling interference by type III CRISPR-Cas. In one coup, these findings resolved two long-standing puzzles of CRISPR biology and reveal a new regulatory pathway that governs the CRISPR response. However, the full extent of this pathway, and especially the driving forces behind the evolution of this complex mechanism of CRISPR-Cas activation, remains to be uncovered.