CRISPR-Cas systems of bacteria and archaea comprise chromosomal loci with typical repetitive clusters and associated genes encoding a range of Cas proteins. Adaptation of CRISPR arrays occurs when virus-derived and plasmid-derived sequences are integrated as new CRISPR spacers. Cas proteins use CRISPR-derived RNA guides to specifically recognize and cleave nucleic acids of invading mobile genetic elements. Apart from this role as an adaptive immune system, some CRISPR-associated nucleases are hijacked by mobile genetic elements: viruses use them to attack their prokaryotic hosts, and transposons have adopted CRISPR systems for guided transposition. In addition, some CRISPR-Cas systems control the expression of genes involved in bacterial physiology and virulence. Moreover, pathogenic bacteria may use their Cas nuclease activity indirectly to evade the human immune system or directly to invade the nucleus and damage the chromosomal DNA of infected human cells. Thus, the evolutionary arms race has led to the expansion of exciting variations in CRISPR mechanisms and functionalities. In this Review, we explore the latest insights into the diverse functions of CRISPR-Cas systems beyond adaptive immunity and discuss the implications for the development of CRISPR-based applications.
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