Lysogeny

Abstract

Lysogeny is the harbouring of a dormant bacteriophage (phage) genome in a growing bacterial host. The well‐studied coliphage lambda system provided the paradigm for the role of regulatory proteins in determining the fate of the infected cell (lysis vs lysogeny) as well as the role of environmental signals that influence this decision. Studies of lambda also led to the classic models for site‐specific integration of phage DNA into the bacterial chromosome and for prophage induction during the SOS response by RecA‐mediated repressor cleavage. Beyond a common requirement for a phage‐encoded repressor to maintain lysogeny, phages other than lambda exhibit substantial diversity in the mechanisms underlying regulation of the lysis/lysogeny decision, integration, and prophage induction. Lysogeny has profound consequences on bacterial evolution, leading to acquisition of new traits, enhanced bacterial fitness, gene disruption and/or genomic rearrangements. Phages that are capable of lysogeny provide a reservoir of genetic diversity for their hosts.

Key Concepts

  • Lysogeny is widespread; prophages are present in ∼1/2 of all sequenced bacterial chromosomes, and many strains carry multiple prophages.
  • Regulation of the phage lysis/lysogeny decision is an example of a bistable gene expression circuit.
  • DNA looping occurs when protein molecules which bind to noncontiguous DNA sites also bind to each other, bringing together DNA sites that are normally some distance apart.
  • Some temperate phages can perpetuate their genomes without integration into the chromosome by plasmid formation, where phage genomes replicate autonomously to keep pace with cell division.
  • Prophage induction is the activation of a prophage to enter the lytic cycle, either spontaneously or by treating lysogenic cells with various agents.
  • Specialised recombination protein machineries are required to establish phage integration. These can be host or phage encoded and bind to dsDNA sequences to catalyse recombination.
  • Site‐specific recombination, which entails breakage and joining of DNA at specific sequences, is used by phages and plasmids and facilitates separation of daughter chromosomes in bacterial cell division.
  • In transposition, some DNA elements, including phage genomes, move from one site to another by action of transposases encoded by the element.
  • Temperate phages provide a mobile genetic reservoir that allows bacteria to adapt to new environments. Prophage‐encoded accessory genes provide new traits that can enhance bacterial fitness or virulence.
  • Lysogeny is transient, allowing bacteria plasticity in their responses to environmental challenges.

Keywords: bacteriophage; integration; repressor; induction; lysogenic conversion

Figure 1. Map of the early regulatory region of bacteriophage lambda, showing the locations of regulatory genes (above the line) and regulatory sites (below the line). Arrows indicate the direction of transcription from each of the promoters. The cI and cro genes encode repressors that bind to operators oL and oR to block transcription from promoters pL and pR during lysogeny and lytic growth, respectively. Each of these operators is composed of three subsites, as indicated. Transcripts initiating from pL and pR are antiterminated by the N gene product, which acts at the nut sites to allow readthrough of terminators tL1, tR1 and expression of the downstream cII and cIII genes. The cII gene product, which is stabilised by cIII, activates transcription from the pE promoter to provide a burst of cI expression needed to establish lysogeny. The pM promoter is both positively and negatively regulated by the cI gene product to maintain repressor levels in a lysogen.
Figure 2. Long‐range cooperativity in repressor occupancy of lambda operator sites. (a) Occupancy of oL2 and oL3 stabilises cooperative binding of CI to oR2 and oR3, thereby enhancing repression of transcription from pR and pL. Interactions between CI bound at oR2 and RNA (ribonucleic acid) polymerase (not shown) also stimulate transcription of cI from pM. As the CI concentration increases, it also binds cooperatively to oL1 and oR1 (b) to repress its own production. This forms a stable feedback loop that maintains sufficient concentrations of CI to sustain lysogeny. Adapted with permission from Dodd et al. 2005 © Elsevier.
Figure 3. Stages of gene expression leading to lambda lysogeny. Regulatory proteins are shown above the line, regulatory sites below. Black arrows show the direction of transcription from the indicated promoters; grey arrows indicate new transcripts produced at each stage. The regulator governing the change in transcription at each stage is highlighted in yellow, with its target indicated by a green arrow if it leads to enhanced expression or a red line if it blocks expression. Not shown, for the sake of simplicity, are the interactions leading to the lytic pathway (inhibition of pM, pL and pR by Cro; antitermination of late gene transcription by Q). Also not shown is posttranscriptional regulation, such as the stabilisation of CII by CIII. The shift from early to delayed early expression, which occurs before lytic/lysogenic commitment, involves antitermination of the two early transcripts by the N protein, which acts at nut sites in the transcripts to allow readthrough of downstream terminators. If expression of cII and cIII leads to the accumulation of sufficient levels of CII before Cro shuts down transcription from pL and pR, the lysogenic pathway is chosen. To establish lysogeny, CII stimulates repressor synthesis from pE, integrase synthesis from pI and an antisense RNA from paQ that blocks expression of the late gene regulator Q. The CI repressor then shuts down transcription from pL and pR and autoregulates its own transcription from pM to maintain lysogeny.
Figure 4. Integration of double‐stranded DNA phages. Phage DNA (deoxyribonucleic acid) and phage‐encoded proteins are shown in black; bacterial DNA and proteins in grey. (a) Overall view of integration by site‐specific recombination into the bacterial chromosome, based on the Campbell model for phage lambda (Campbell, ). The flanking left and right arms of the bacterial (B and B′; pink) and phage (P and P′; red) attachment sites and the conserved core (O; white) are indicated to illustrate the formation of the two hybrid att sites flanking the integrated lambda genome. The first step in integration is the formation of a circular DNA molecule. In the case of lambda, this involves annealing of complementary overhangs present at the ends of the linear virion DNA. Some other phages accomplish circularisation via homologous recombination between terminally redundant sequences. Integration is catalysed by the phage‐encoded Int protein in concert with the host‐encoded IHF and Fis proteins. The reverse reaction also requires the phage‐encoded Xis protein. (b) The pathway of Mu integration by transposition. The linear Mu virion DNA contains bacterial chromosomal DNA from its previous host at either end. The Mu‐encoded N protein (black circle) binds to the ends of the donor sequence to convert the Mu genome to a noncovalent circular, supercoiled form. The MuA transposase and its coregulator MuB capture the random target sequence (green). MuA catalyses hydrolytic cleavage of phosphodiester bonds at the ends of the Mu sequence to generate free 3′‐OH groups that participate in nucleophilic attack of target sequences (dashed arrows). Protein N is subsequently displaced by host ClpX and RecBCD, DNA sequence from the donor bacterium is removed (not shown) and gaps in the target sequence are synthesised by limited DNA replication using host replication fork machinery.
Figure 5. Integration of single‐stranded DNA phages. In some cases, the ssDNA phage genome (black) is converted to its double‐stranded replicative form (a and b), generating dsDNA sequences that engage distinct recombination protein machineries and accessory factors to facilitate homologous recombination (black: phage encoded, grey: host encoded). (a) attP (pink) recruits Integrase (Int), which catalyses recombination with specific bacterial attB sites (red). Excision is mediated by Xis in addition to Int. The involvement of specific host accessory proteins in this process has not yet been clearly established. (b) dif sequences present in both the phage and bacterial chromosomes (yellow) recruit the host XerC/XerD machinery; in some cases, XerC/XerD has also been shown to mediate excision. (c) The ssDNA form of CTXϕ engages XerC/XerD machinery using a dif‐like sequence (dif*) that is created by DNA secondary structure formation between two phage sequences (blue and purple). Recombination with the host dif sequence leads to integration of the ssDNA phage genome. When this is subsequently converted to dsDNA in the host chromosome, the dif* sequence is masked – neither of the contributing half sequences (blue or purple) is itself a dif site when double stranded – and the integrated phage is therefore not a substrate for XerC/XerD‐mediated excision.
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Further Reading

Brussow H, Canchaya C and Hardt WD (2004) Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiology and Molecular Biology Reviews 68: 560–602.

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Ptashne M (1992) A Genetic Switch, New edn. Cambridge, MA: Cell Press and Blackwell.

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Tan, Jason A, and Christie, Gail E(Jul 2017) Lysogeny. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000780.pub3]