Adapting to new threats: the generation of memory by CRISPR‐Cas immune systems

Abstract

Summary Clustered, regularly interspaced, short palindromic repeats (CRISPR) loci and their associated genes (cas) confer bacteria and archaea with adaptive immunity against phages and other invading genetic elements. A fundamental requirement of any immune system is the ability to build a memory of past infections in order to deal more efficiently with recurrent infections. The adaptive feature of CRISPR-Cas immune systems relies on their ability to memorize DNA sequences of invading molecules and integrate them in between the repetitive sequences of the CRISPR array in the form of “spacers”. The transcription of a spacer generates a small antisense RNA that is used by RNA-guided Cas nucleases to cleave the invading nucleic acid in order to protect the cell from infection. The acquisition of new spacers allows the CRISPR-Cas immune system to rapidly adapt against new threats and is therefore termed “adaptation”. Recent studies have begun to elucidate the genetic requirements for adaptation and have demonstrated that rather than being a stochastic process, the selection of new spacers is influenced by several factors. We review here our current knowledge of the CRISPR adaptation mechanism.

CRISPR–Cas9 Structures and Mechanisms

“…Many bacteria and most archaea have evolved sophisticated RNA-guided adaptive immune systems encoded by CRISPR loci and the accompanying CRISPR-associated (cas) genes to provide acquired immunity against bacteriophage infection and plasmid transfer (Figure 1a) (31,66,71). During the immunization process following exposure to invading genetic elements from phage or plasmids, short fragments of foreign DNA are integrated into the CRISPR repeat-spacer array within the host chromosome as new spacers (1), thereby providing a genetic record of prior infection that enables the host to prevent future invasion of the same invader (5,63).…”

Nuclease Activity of Legionella pneumophila Cas2 Promotes Intracellular Infection of Amoebal Host Cells

“…In L. pneumophila, there is a type II-B locus that has a CRISPR array with 60 repeats and 58 unique spacers and a cas operon consisting of cas9, cas1, cas2, and cas4 (15). CRISPR-Cas-mediated immunity proceeds in three steps: first, a new spacer derived from an invading genetic element is incorporated into the CRISPR array via the action of Cas1 and Cas2; second, the array is transcribed, and small CRISPR RNAs (crRNAs) are generated by Cas6 homologs or RNase III; and third, the crRNAs direct other Cas nucleases to cleave newly invading nucleic acid (19,20,23,24).Our finding that Cas2 mutants of L. pneumophila have an impaired ability to infect host cells was part of an initial shift in …”

“…The Cas2 family of proteins is best known for being part of the bacterial and archeal clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein (Cas) system, a recently described system that confers immunity against phage and plasmid (19)(20)(21). Present in the genomes of nearly all archaea and the genomes of approximately one-half of bacteria, the CRISPR-Cas locus consists of the CRISPR array, which is composed of a variable number of palindromic repeats separated by unique spacer sequences, and a set of cas genes which encodes a variable number of Cas proteins.…”

Occurrence of Small Homologous and Complementary Fragments in Human Virus Genomes and Their Possible Role

“…Как известно, существующая у бактерий и ар-хей адаптивная защитная система CRISPR/Cas построена на механизме включения в их геном коротких фрагментов генома поражающих их вирусов и использования транскриптов с этих фрагментов для специфической посадки на ге-ном вторгнувшегося вируса нуклеазы, расщепля-ющей его [5,7]. Открытие CRISPR/Cas свидетель-ствует о том, что способность распознавания «не-своего» и защита от него возникла уже на самых ранних этапах эволюции и представлена множе-ством механизмов.…”