CRISPR, an adaptive anti-viral defense system in prokaryotes

We study aspects of CRISPR-Cas, the adaptive anti-viral defense system in prokaryotes. This system is composed of arrays of regularly interspaced short DNA repeats that are separated by similarly sized non-repetitive spacers. CRISPR arrays, together with a group of associated proteins, confer resistance to phages (Nature Reviews Microbiology 2008, Annual Reviews In Biochemistry 2013, Nature Reviews Microbiology 2016, Science 2017, Nature 2018).

We use high throughput genomics, computational and experimental tools to study the CRISPR-Cas system. Early on we discovered that secondary structures within CRISPR repeats play a role in CRISPR-Cas biology (Kunin et al 2007). We also found that the CRISPR-Cas system can make "mistakes" and target its host genome, leading to curious "autoimmunity" phenotypes in bacteria (Stern et al 2010). Using CRISPR arrays of bacteria that inhabit the human gut microbiome, we found almost 1000 phages the infect human gut bacteria, and showed that these phages are shared among geographically distant human populations (Stern, Mick et al 2012). Our studies have also deciphered the mechanism by which the CRISPR-Cas system differentiates between "self" and "foreign" DNA during the adaptation stage (Levy et al, Nature 2015).

a) Typical structure of a clustered, regularly interspaced short palindromic repeat (CRISPR) locus. b) CRISPRs acquire phage-derived spacers that provide immunity. Following an attack by a phage, phage nucleic acids proliferate in the cell and new particles are produced, leading to the death of the majority of the sensitive bacteria. A small number of bacteria acquire phage-derived spacers (marked by an asterisk), leading to survival, by CRISPR-mediated degradation of phage DNA or RNA. c) A simplified model for CRISPR-Cas action. The repeat-spacer array is transcribed into a long RNA, and the repeats assume a secondary structure. Cas proteins recognize the sequence or structure of the repeats and process the RNA to produce small RNAs (sRNAs), each of which contains a spacer and parts of the repeats. The sRNAs, complexed with additional Cas proteins, base pair with phage nucleic acids, leading to their degradation. This process is mediated by several Cas proteins that are complexed with the sRNA. CAS, CRISPR-associated. (Figure taken from Sorek et al., Nature Reviews Microbiology, (2008))