Chapter 2 : Iteron Plasmids

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Iteron plasmids are extrachromosomal genetic elements that can be found in all Gram-negative bacteria. Despite the fact that these plasmids bring antibiotic resistance to host bacterium, they can also bring other features, for example, genes for degradation of specific compounds or toxin production. Iteron plasmids possess characteristic directed repeats located within the origin of replication initiation that are called iterons. These plasmids became model systems for investigation of the molecular mechanisms for DNA replication initiation and for the analysis of mechanisms of control of plasmid copy number in bacterial cells. This research has provided our basic understanding of plasmid biology and the relationship between plasmid DNA and host cells. The control mechanisms utilized by iteron plasmids are based on the nucleoprotein complexes formed by the plasmid-encoded replication initiation protein (Rep). The Rep proteins interact with iterons, which initiates the process of plasmid DNA synthesis, but Rep proteins are also able to form complexes with iterons, which inhibits the replication initiation process. This inhibition is called “handcuffing.” Also, Rep protein can interact with inverted repeated sequences, causing transcriptional auto-repression. Finally, various chaperone protein systems and proteases affect the Rep activity and, therefore, overall plasmid DNA metabolism.

Citation: Konieczny I, Bury K, Wawrzycka A, Wegrzyn K. 2015. Iteron Plasmids, p 33-44. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0026-2014
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Figure 1

Scheme of the iteron-containing plasmid origin structure. The direct repeats—iterons—and inverted repeats (IR) are depicted as red arrows. The DUE region of each origin is marked, and repeated sequences within the region are depicted as green triangles. DnaA-box sequences are marked in blue. The region rich in guanidine and cytidine residues (GC-rich) is marked within the origins, if identified. The origins are not drawn to scale.

Citation: Konieczny I, Bury K, Wawrzycka A, Wegrzyn K. 2015. Iteron Plasmids, p 33-44. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0026-2014
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Figure 2

Structure of replication initiators. DnaA of , RepE54 from mini-F plasmid, π from R6K, and the C-terminal part of the TrfA protein (190-382 aa) of plasmid RK2 are depicted. Structure of the DnaA, RepE54, and π are derived from crystallographic data (PDB entry 1L8Q, 1REP, and 2NRA, respectively). The TrfA model was developed based on homology modeling. The AAA+ domain is colored in blue, the DNA binding domain (DBD) is shown in red, and Winged-Helix domains (WH1 and WH2) are colored in yellow and green, respectively. References and detailed information for crystallographic data of the DnaA, RepE54, π, and TrfA model are given in the text.

Citation: Konieczny I, Bury K, Wawrzycka A, Wegrzyn K. 2015. Iteron Plasmids, p 33-44. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0026-2014
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Figure 3

Model of replication initiation: comparison of the processes occurring on the iteron-containing plasmid origin with the replication initiation of bacterial chromosomes. The iteron-containing plasmid origin is recognized by the plasmid-encoded initiator (Rep), which binds cooperatively to the iterons. The interaction of Rep with iterons results in the formation of an open complex and destabilization of the DNA unwinding element (DUE), which creates ssDNA. In RK2, pPS10, F, R6K, P1, and pSC101 the formation of the open complex requires cooperation of the plasmid Rep and host DnaA proteins, while at the chromosomal origin the DnaA protein is sufficient for this process. During the chromosomal origin opening DnaA forms filament on the ssDNA. Helicase delivery and loading requires interaction with the replication initiators; in addition, in the DnaB helicase delivery at the chromosomal as well as at the plasmid RK2 requires the DnaC accessory protein. During the RK2 replication initiation in the host-encoded DnaBC helicase complex is delivered to the DnaA-box sequence through interaction with DnaA, and subsequently the plasmid initiator TrfA translocates the helicase to the opened plasmid origin. The interactions between DnaB and the R6K π protein, F RepE, and pSC101 RepA have also been established as essential for helicase complex formation at the plasmids’ origins. The helicase unwinds the DNA double helix, and after a short RNA fragment is synthesized by a primase, a polymerase complex is assembled. Single-stranded DNA binding protein (SSB) is required for replication initiation of both chromosomal and iteron-containing plasmid DNA. The HU/IHF proteins’ contribution in DNA replication initiation was omitted in the scheme. For a detailed description see the text.

Citation: Konieczny I, Bury K, Wawrzycka A, Wegrzyn K. 2015. Iteron Plasmids, p 33-44. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0026-2014
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Figure 4

Regulation of iteron-containing plasmid replication initiation by the iterons. Rep protein activation occurs by the action of chaperones that convert the Rep dimer to the active monomeric form. Monomers bind to the iteron sequences and perform the initial complex that leads to replication of DNA. Rep protein may also act as a negative regulator of DNA replication by creating “handcuff” structures. Rep proteins couple origins of two separate plasmid particles in a process termed “handcuffing.” In the literature suggestions of chaperone proteins’ participation in the “uncuffing” process can be found, but the mechanism of the handcuff structures’ reversal is still unclear. For details see the text.

Citation: Konieczny I, Bury K, Wawrzycka A, Wegrzyn K. 2015. Iteron Plasmids, p 33-44. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0026-2014
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Figure 5

Regulation of iteron-containing plasmid replication initiation by the auto-repression mechanism. Binding of Rep dimers to inverted repeats inhibits the initiation of transcription starting from the gene promoter. This phenomenon is called auto-repression. An active, monomeric form of Rep protein arises as a result of the action of chaperones. It binds to the iteron sequences that lead to the initiation of DNA replication. Proteases are another factor that may influence the replication process. They limit the amount of both dimer and monomer forms of the Rep protein. For details see the text.

Citation: Konieczny I, Bury K, Wawrzycka A, Wegrzyn K. 2015. Iteron Plasmids, p 33-44. In Tolmasky M, Alonso J (ed), Plasmids: Biology and Impact in Biotechnology and Discovery. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.PLAS-0026-2014
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