Diversity of molecular mechanisms used by anti-CRISPR proteins: the tip of an iceberg?

Bacteriophages (phages) and their preys are engaged in an evolutionary arms race driving the co-adaptation of their attack and defense mechanisms. In this context, phages have evolved diverse anti-CRISPR proteins to evade the bacterial CRISPR–Cas immune system, and propagate. Anti-CRISPR proteins do not share much resemblance with each other and with proteins of known function, which raises intriguing questions particularly relating to their modes of action. In recent years, there have been many structure–function studies shedding light on different CRISPR–Cas inhibition strategies. As the anti-CRISPR field of research is rapidly growing, it is opportune to review the current knowledge on these proteins, with particular emphasis on the molecular strategies deployed to inactivate distinct steps of CRISPR–Cas immunity. Anti-CRISPR proteins can be orthosteric or allosteric inhibitors of CRISPR–Cas machineries, as well as enzymes that irreversibly modify CRISPR–Cas components. This repertoire of CRISPR–Cas inhibition mechanisms will likely expand in the future, providing fundamental knowledge on phage–bacteria interactions and offering great perspectives for the development of biotechnological tools to fine-tune CRISPR–Cas-based gene edition.