Matvey Kolesnik, Iana Fedorova, Karyna Karneyeva, Daria Artamonova and Konstantin Severinov have published a comprehensive review “Type III CRISPR-Cas Systems: Deciphering the Most Complex Prokaryotic Immune System” in Biochemistry (Moscow) journal. Type III CRISPR-Cas systems are among the most common CRISPR-Cas systems and specifically recognize and cleave RNA molecules. The recognition of the target RNA activates the effector large subunit – the so-called CRISPR polymerase – which cleaves DNA and produces small cyclic oligonucleotides that act as signaling molecules to activate downstream effectors. In this paper, the researchers provide a historical overview of the sometimes meandering pathway of the Type III CRISPR research. They also review the current data on the structures and activities of Type III CRISPR-Cas systems components, their biological roles, and evolutionary history. The researchers also used structural modelling via AlphaFold2 showed that the archaeal HRAMP signature protein, which heretofore has had no assigned function, is a degenerate relative of Type III CRISPR-Cas signature protein Cas10, suggesting that HRAMP systems have descended from Type III CRISPR-Cas systems or their ancestors. Full text of the review is available here.