title: BREX is a novel phage resistance system widespread in microbial genomes.
abstract: The perpetual arms race between bacteria and phage has resulted in the evolution of efficient resistance systems that protect bacteria from phage infection. Such systems, which include the CRISPR-Cas and restriction-modification systems, have proven to be invaluable in the biotechnology and dairy industries. Here, we report on a six-gene cassette in Bacillus cereus which, when integrated into the Bacillus subtilis genome, confers resistance to a broad range of phages, including both virulent and temperate ones. This cassette includes a putative Lon-like protease, an alkaline phosphatase domain protein, a putative RNA-binding protein, a DNA methylase, an ATPase-domain protein, and a protein of unknown function. We denote this novel defense system BREX (Bacteriophage Exclusion) and show that it allows phage adsorption but blocks phage DNA replication. Furthermore, our results suggest that methylation on non-palindromic TAGGAG motifs in the bacterial genome guides self/non-self discrimination and is essential for the defensive function of the BREX system. However, unlike restriction-modification systems, phage DNA does not appear to be cleaved or degraded by BREX, suggesting a novel mechanism of defense. Pan genomic analysis revealed that BREX and BREX-like systems, including the distantly related Pgl system described in Streptomyces coelicolor, are widely distributed in ~10% of all sequenced microbial genomes and can be divided into six coherent subtypes in which the gene composition and order is conserved. Finally, we detected a phage family that evades the BREX defense, implying that anti-BREX mechanisms may have evolved in some phages as part of their arms race with bacteria.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tamara
authors.initials: T
authors.lastname: Goldfarb
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Sberro
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: Weinstock
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ofir
authors.initials: O
authors.lastname: Cohen
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shany
authors.initials: S
authors.lastname: Doron
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Charpak-Amikam
authors.affiliation: Computational Biology Graduate Group, University of California Berkeley, Berkeley, CA, USA.
authors.forename: Shaked
authors.initials: S
authors.lastname: Afik
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Ofir
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel rotem.sorek@weizmann.ac.il.
authors.forename: Rotem
authors.initials: R
authors.lastname: Sorek
mesh_terms: D001412:Bacillus subtilis / Q000235:genetics / Q000821:virology*; D001435:Bacteriophages / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity*; D005075:Biological Evolution; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D004269:DNA, Bacterial / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D064349:Genome, Microbial; D010802:Phylogeny; D014774:Virulence / Q000235:genetics*
chemical_list: D004269:DNA, Bacterial; D004279:DNA, Viral; D015254:DNA Modification Methylases
keywords: CRISPR; PGL; pglZ; phage defense