The par locus of the Enterococcus faecalis plasmid pAD1 is an RNA-regulated addiction module encoding the peptide toxin Fst. Homology searches revealed that Fst belongs to a family of at least nine related peptides encoded on the chromosomes and plasmids of six different Grampositive bacterial species. Comparison of an alignment of these peptides with the results of a saturation mutagenesis analysis indicated regions of the peptides important for biological function. Examination of the genetic context of the fst genes revealed that all of these peptides are encoded within par-like loci with conserved features similar to pAD1 par. All four Ent. faecalis family members were demonstrated to produce the expected toxin-encoding and regulatory RNA products. The locus from the Ent. faecalis plasmid pAMS1 was demonstrated to function as an addiction module and Fst was shown to be toxic to Staphylococcus aureus, suggesting that a plasmid-encoded module in that species is performing the same function. Thus, the pAD1-encoded par locus appears to be the prototype of a family of related loci found in several Grampositive species. INTRODUCTIONToxin-antitoxin (TA) systems were first identified on bacterial plasmids, where they function as stability determinants by programming for death any daughter cells that fail to inherit a copy (for recent reviews see Gerdes & Wagner, 2007;Hayes, 2003). These systems, originally called post-segregation killing systems or addiction modules, encode a stable toxin and an unstable antitoxin. As long as the plasmid is properly inherited, antitoxin is continually replenished and the toxin remains inactive. If the plasmid is lost, the antitoxin is degraded and the toxin is free to exert its effect. Toxins have a variety of targets including gyrase (Bahassi et al., 1999;Jiang et al., 2002), ribosome-bound and free mRNA (Condon, 2006;Zhang et al., 2004), and the cell membrane (Gerdes et al., 1986). In most TA systems, both components are proteins, with the antitoxin targeted by a specific cellular protease (Gerdes et al., 2005). In two well-studied cases, the hok/sok system of Escherichia coli plasmid R1 (Gerdes et al., 1990) and the par system of Enterococcus faecalis plasmid pAD1 Greenfield et al., 2001, the antitoxin is a small regulatory RNA that represses the translation of the toxin. The RNA-regulated TA systems are sometimes referred to as type I TA loci while the proteinregulated systems are designated type II.Paradoxically, numerous TA systems have been identified on bacterial chromosomes and have been the subject of numerous recent reviews (Buts et al., 2005; EngelbergKulka et al., 2006;Fozo et al., 2008;Gerdes & Wagner, 2007;Gerdes et al., 2005;Van Melderen & Saavedra De Bast, 2009). Various roles have been either demonstrated or proposed for these systems, including stabilization of integrated mobile genetic elements, protection from plasmid-encoded addiction modules, programmed cell death, growth modulation during stress response, persistence, and developmental processes. It seems like...
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