Bacteriophages (phages) and other mobile genetic elements (MGEs) exert an immense selective pressure on     1    (bacterium), which in response have developed a broad arsenal of defence mechanisms.     2     these, CRISPR–Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated proteins) is a group of widespread RNA-guided adaptive immune systems that are classified into two broad classes, six types and numerous subtypes according to their genetic composition and interference mechanism1. The CRISPR–Cas immune response starts with the    3    (acquire) of short DNA fragments (protospacers) from invading MGEs. The protospacers are inserted as spacers between repeats in the CRISPR array to create a memory of the infection. Next, the CRISPR array is expressed    4     a long transcript that is processed into small, mature CRISPR RNAs (crRNAs), each    5    (carry) a spacer sequence flanked by part of the repeat. Finally, the interference complexes, composed     6     a crRNA and one (class 2) or more (class 1) Cas proteins, degrade the complementary nucleic-acid targets that are often found next to a short protospacer-adjacent motif (PAM). The specificity and programmability of the CRISPR–Cas machinery     7    (lead) to the development of various biotechnological applications in genome editing, molecular diagnostics and more.

In the evolutionary arms race with CRISPR–Cas, phages and other MGEs have evolved diverse strategies to block or circumvent immunity. One widespread evasion mechanism uses protein-    8    (base) CRISPR–Cas inhibitors called anti-CRISPRs (Acrs). So far, more than 100 Acr protein families have been identified    9     inhibit different stages of the CRISPR–Cas immune response, mainly by interacting directly with Cas proteins. For example, Acrs prevent crRNA loading, effector-complex formation, and target DNA binding and cleavage. Notably, the discovery of these natural ‘off switches’ has presented new opportunities    10    (control) the activity of CRISPR–Cas technologies.