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Mechanisms of Plasmid Stable Maintenance with Special Focus on Plasmid Addiction Systems

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Mechanisms of Plasmid Stable Maintenance with Special Focus on Plasmid Addiction Systems Vol. 48 No. 4/2001 1003–1023 QUARTERLY Review Mechanisms of plasmid stable maintenance with special focus on plasmid addiction systems. ½ Urszula Zielenkiewicz and Piotr Ceg³owski Institute of Biochemistry and Biophysics, Polish Academy of Sciences Received: 5 November, 2001, accepted: 24 November, 2001 Key words: plasmid addiction, post-segregational killing, partition; multimer resolution The stable inheritance of bacterial plasmids is achieved by a number of different mechanisms. Among them are resolution of plasmid oligomers into monomers, active plasmid partitioning into dividing cells and selective killing of plasmid-free segre- gants. A special focus is given to the last mechanism. It involves a stable toxin and an unstable antidote. The antidotes neutralize their cognate toxins or prevent their syn- thesis. The different decay rates of the toxins and the antidotes underlie molecular mechanisms of toxin activation in plasmid-free cells. By eliminating of plasmid-free cells from the population of plasmid-bearing ones the toxin-antidote couples therefore act as plasmid addiction systems. Plasmids are separate, autonomous genetic burgdorferi, Fraser et al., 1997; Bacillus cereus, elements present in a cell independently of Carlson & Kolstø, 1994). It is commonly ac- chromosomes. Most plasmids are small: from cepted that plasmid genes do not encode infor- several to 100 kb, but sometimes they are so mation indispensable for the functioning of large that using the size criteria their distinc- the host cell. However, plasmids specify nu- tion from the chromosome is difficult (e.g. in merous features advantageous for the host in Vibrio cholerae, Yamaichi et al., 1999; in specific environments, such as resistance to Rhizobium meliloti, Honeycutt et al., 1993). harmful agents, ability to degrade rare com- Different plasmids can constitute even up to pounds, pathogenicity, toxin production, ni- 50% of bacterial DNA (e.g. in Borrelia trogen assimilation etc. This work was supported by the State Committee for Scientific Research (KBN, Poland) grant No. 6 P04B 008 20 ½ Corresponding author: Doc. Piotr Ceg³owski, Institute of Biochemistry and Biophysics, A. Pawiñskiego 5a, 02-106 Warszawa, Poland; tel.: (48 22) 658 4723; fax.: (48 22) 658 3646; e-mail: [email protected] 1004 U. Zielenkiewicz and P. Ceg³owski 2001 Plasmids are very widely distributed among A—site-specific recombination systems Prokaryota and, in general, are inherited with ensuring that plasmid multimers arisen dur- a high degree of stability. In special environ- ing replication and(or) recombination will be mental conditions some plasmid genes confer resolved and thus every monomer copy will be a selective advantage. But, in many cases, independently subjected to random distribu- plasmids are retained over generations with- tion; out any selective pressure. Thus, there have to B—active partition process which pre- exist mechanisms which enable the mainte- cisely distributes plasmid copies to each nance of the plasmid during cell growth in daughter cell at division; nonselective conditions. Systems that contrib- C—plasmid addiction systems, e.g. func- ute to this stability are encoded by DNA cas- tions that kill or reduce growth of plasmid- settes and are, in most cases, independent of free descendant cells. one another. A particular plasmid can carry While mechanisms described in class A lead different stabilizing cassettes. Even more, to the optimization of random plasmid distri- cassettes from different plasmids may be com- bution, class B and C mechanisms ensure bined to give a stable replicon. better than random plasmid inheritance. RANDOM- AND BETTER-THAN- SITE-SPECIFIC RECOMBINATION RANDOM PLASMID DISTRIBUTION SYSTEMS During the process of cell division plasmid Identical copies of a given plasmid fre- copies are distributed between two descen- quently form oligomers. This reduces the dants. If plasmid distribution within a grow- number of independent units during segrega- ing cell is random, in the “ideal replicon”, it is tion. Moreover, since origins of plasmid repli- the number of plasmid molecules inside the di- cation are selected at random (Summers et al., viding cell that determines the probability 1993), the probability that plasmid monomers (P0) that one of the daughters will be plasmid will be selected for replication is, for instance, (1–n) free (Nordström & Austin, 1989): P0 =2 two-fold lower than for plasmid dimers. Con- , where n is the number of plasmid copies. sequently, dimers will out-replicate mono- Therefore, a cell having 30 plasmid copies at mers. The outcome of this ‘dimer catastrophe’ the time of division would produce in 109 cells (Summers et al., 1993) would be a consider- only two plasmid-free ones, whereas in the able plasmid loss from the host cells. To en- case of 5 copies, the chance of giving a sure a plasmid distribution process to be plasmid-free cell is as much as 1 per 16. highly efficient, there is a need for every As long as the plasmid copy number remains plasmid copy to be accessible for distribution. high, the subpopulation of plasmid-free cells is This is achieved by site-specific recombination extremely limited. For low copy number systems, also called mrs — multimer reso- plasmids obeying the random distribution law lution systems. In this process plasmid oligo- would mean that a significant fraction of mers naturally formed during replication or daughter cells will be plasmid free. This is in recombination are resolved into monomers in- contrast to the observed maintenance of creasing the number of independent mole- plasmids in the host cells. Several mecha- cules accessible for distribution. nisms have been proposed, and shown to oper- The multimer resolution systems consist ate, to explain this discrepancy (see below). of a site-specific recombinase, so called resol- They can be divided into three classes: A, B vase, and the defined nucleotide sequence res and C. located on the plasmid. By specific recombina- Vol. 48 Plasmid stable maintenance 1005 tion between repeated res sequences, the is very efficient (for example: the probability recombinase resolves oligomers to mono- of loss of P1 prophage, which is present as one mers. The mrs systems can be encoded en- extrachromosomal unit in the cell, is <1in tirely by the plasmid (e.g. loxP-cre of P1; Aus- 105 per generation; Abeles et al., 1985). tin et al., 1981) or combine the res site of the Models for the active partitioning process in- plasmid with a host encoded recombinase clude the pairing of plasmid molecules at (e.g. cer of ColE1 and host xerC, xerD, argR, cis-acting sites and subsequent separation of pepA; Summers & Sherrat, 1984; Sharpe et single plasmid copies to the opposite poles of al., 1999). the cell. The involvement of cellular compo- The multimer resolution systems of the nents in the process of plasmid separation is inc18 plasmid family from Gram-positive bac- proposed (Watanabe et al., 1989; Bignell et teria, although encoded by plasmids, require al., 1999). the host factor Hbsu to mediate resolution The partition process is carried out by two (Rojo & Alonso, 1994; Alonso et al., 1995; proteins usually designated as A and B. The Janniére et al., 1996). genetic organization of various partition sys- In the majority of high-copy number tems is similar, with the gene for the A pro- plasmids, the multimer resolution system is tein preceding the protein B-encoding gene the sole additional mechanism influencing and an adjacent centromere-like DNA se- their stable inheritance (for a review see quence. As an example, the structure of the Nordstrom & Austin, 1989; Hiraga, 1992; partition operon of P1 plasmid is shown Summers, 1998). In combination with the (Fig. 1). copy number and cell division control it en- The partition operons are negatively sures a very low frequency of plasmid loss. autoregulated by protein A (i.e. plasmids P1, F) or protein B (i.e. plasmids NR1, R1, pTAR). The repressor activity of one protein can be ACTIVE PARTITION enhanced by the other. The tight regulation of par operons expression is very important Many plasmids, especially those having mod- since an excess of protein B leads to plasmid erate or low copy number, possess an active destabilization (i.e. SopB of F plasmid; (i.e. energy consuming) mechanism for pre- Kusukawa et al., 1987; ParB of P1; £obocka & Figure 1. Schematic representation of the par operon organization of P1 plasmid. The promoter–operator parPO and parS regions are blown up. Binding sites for ParB protein are boxed. Broken ar- row indicates the promoter. cise distribution prior to cell division of avail- Yarmolinsky, 1996). Protein B excess can also able plasmid copies to prospective daughter silence genes flanking the cis-acting sites (up cells. This process, named by analogy to chro- to several kilobases away) by polymerization mosome partitioning, as active partitioning, along the DNA starting from a certain point, 1006 U. Zielenkiewicz and P. Ceg³owski 2001 as has been shown for SopB (Lynch & Wang, bacteria, including Bacillus subtilis, Caulo- 1995) and ParB (Rodionov et al., 1999). bacter crescentus and Pseudomonas putida. All three components, partition proteins A, Their role in chromosome segregation has B and par site, are required for partition. The been shown for example in B. subtilis (locus ParB proteins bind specifically to their cog- soj-spo0J; Sharpe & Errington, 1996; 1998) or nate cis-acting DNA sequences termed centro- C. crescentus (genes parA, parB and parS; mere-like regions (Mori et al., 1989; Watanabe Mohl & Gober, 1997). In spite of a functional et al., 1989). These cis-acting sites are located similarity between chromosome and plasmid downstream (plasmids P1, F, RK2) or up- partitioning these two processes proceed dis- stream (NR1, R1, pTAR) from par genes. tinctly (Gordon et al., 1997). Their structure is unique for different plasmids, but always contains a characteristic number of iterated repeats which are the sites PLASMID ADDICTION SYSTEMS for specific binding of protein B.
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