Faculty Opinions recommendation of Self versus non-self discrimination during CRISPR RNA-directed immunity.
Year: 2010
Type: peer-review
Abstract: All immune systems must distinguish self from non-self to repel invaders without inducing autoimmunity.Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci protect bacteria and archaea from invasion by phage and plasmid DNA through a genetic interference pathway 1 -9 .CRISPR loci are present in ~ 40% and ~90% of sequenced bacterial and archaeal genomes respectively 10 and evolve rapidly, acquiring new spacer sequences to adapt to highly dynamic viral populations 1 , 11 -13 .Immunity requires a sequence match between the invasive DNA and the spacers that lie between CRISPR repeats 1 -9 .Each cluster is genetically linked to a subset of the cas (CRISPR-associated) genes 14 -16 that collectively encode >40 families of proteins involved in adaptation and interference.CRISPR loci encode small CRISPR RNAs (crRNAs) that contain a full spacer flanked by partial repeat sequences 2 , 17 -19 .CrRNA spacers are thought to identify targets by direct Watson-Crick pairing with invasive "protospacer" DNA 2 , 3 , but how they avoid targeting the spacer DNA within the encoding CRISPR locus itself is unknown.Here we have defined the mechanism of CRISPR self/non-self discrimination.In Staphylococcus epidermidis, target/crRNA mismatches at specific positions outside of the spacer sequence license foreign DNA for interference, whereas extended pairing between crRNA and CRISPR DNA repeats prevents autoimmunity.Hence, this CRISPR system uses the base-pairing potential of crRNAs not only to specify a target but also to spare the bacterial chromosome from interference.Differential complementarity outside of the spacer sequence is a built-in feature of all CRISPR systems, suggesting that this mechanism is a broadly applicable solution to the self/nonself dilemma that confronts all immune pathways.S. epidermidis strain RP62a (ref.20 ) contains a CRISPR locus that includes a spacer (spc1) that is identical to a region of the nickase (nes) gene found in nearly all sequenced staphylococcal conjugative plasmids (Fig. 1a and Supplementary Fig. 1a), including those Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.
Authors: Michael McManus, Nikki Shariat
Institution: University of California, San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4205713857