Anti-CRISPR proteins: a weapon of phage-bacterial arm race for genome editing

The ongoing evolutionary competition between bacteria and their phage parasites has led to the development of intricate systems of attacks, defenses, and counter-defenses. Among the prokaryotic adaptive immunity measures, the CRISPR–Cas system has garnered significant attention for its versatility in genome editing and other biotechnological applications. In this system, bacteria capture specific sequences from invading phages and store them in their genome as a record. This allows the bacteria to recognize and target the phage DNA for degradation using Cas proteins upon subsequent infections. On the phage side of the battle, a counter mechanism known as ‘Anti-CRISPR’ (Acr) has emerged. Acr proteins, encoded by phages or Mobile Genetic Elements (MGEs), function to inhibit CRISPR–Cas activity. They achieve this by either blocking DNA binding or inhibiting the cleavage process of the CRISPR–Cas effector complexes. Acrs present the potential to develop regulated and reversible CRISPR–Cas-mediated gene circuits, opening up possibilities for precise genome editing. Researchers are exploring the applications of Acrs to reduce off-target mutations associated with CRISPR–Cas, modulate the activities of Cas endonucleases, and create “genome safeguard” systems where further editing is restricted. The study and utilization of Acrs hold promise for advancing the precision and control of CRISPR–Cas technologies. Graphical abstract Enhancing CRISPR with Anti-CRISPR Protein