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Processive Antitermination

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  • Authors: Jonathan R. Goodson1, Wade C. Winkler2
  • Editors: Gisela Storz3, Kai Papenfort4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Cell Biology and Molecular Genetics, The University of Maryland, College Park, MD 20742; 2: Department of Cell Biology and Molecular Genetics, The University of Maryland, College Park, MD 20742; 3: Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD; 4: Department of Biology I, Microbiology, LMU Munich, Martinsried, Germany
  • Source: microbiolspec September 2018 vol. 6 no. 5 doi:10.1128/microbiolspec.RWR-0031-2018
  • Received 24 April 2018 Accepted 12 July 2018 Published 07 September 2018
  • Wade C. Winkler, [email protected]
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  • Abstract:

    Transcription is a discontinuous process, where each nucleotide incorporation cycle offers a decision between elongation, pausing, halting, or termination. Many -acting regulatory RNAs, such as riboswitches, exert their influence over transcription elongation. Through such mechanisms, certain RNA elements can couple physiological or environmental signals to transcription attenuation, a process where -acting regulatory RNAs directly influence formation of transcription termination signals. However, through another regulatory mechanism called processive antitermination (PA), RNA polymerase can bypass termination sites over much greater distances than transcription attenuation. PA mechanisms are widespread in bacteria, although only a few classes have been discovered overall. Also, although traditional, signal-responsive riboswitches have not yet been discovered to promote PA, it is increasingly clear that small RNA elements are still oftentimes required. In some instances, small RNA elements serve as loading sites for cellular factors that promote PA. In other instances, larger, more complicated RNA elements participate in PA in unknown ways, perhaps even acting alone to trigger PA activity. These discoveries suggest that what is now needed is a systematic exploration of PA in bacteria, to determine how broadly these transcription elongation mechanisms are utilized, to reveal the diversity in their molecular mechanisms, and to understand the general logic behind their cellular applications. This review covers the known examples of PA regulatory mechanisms and speculates that they may be broadly important to bacteria.

  • Citation: Goodson J, Winkler W. 2018. Processive Antitermination. Microbiol Spectrum 6(5):RWR-0031-2018. doi:10.1128/microbiolspec.RWR-0031-2018.

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/content/journal/microbiolspec/10.1128/microbiolspec.RWR-0031-2018
2018-09-07
2018-11-19

Abstract:

Transcription is a discontinuous process, where each nucleotide incorporation cycle offers a decision between elongation, pausing, halting, or termination. Many -acting regulatory RNAs, such as riboswitches, exert their influence over transcription elongation. Through such mechanisms, certain RNA elements can couple physiological or environmental signals to transcription attenuation, a process where -acting regulatory RNAs directly influence formation of transcription termination signals. However, through another regulatory mechanism called processive antitermination (PA), RNA polymerase can bypass termination sites over much greater distances than transcription attenuation. PA mechanisms are widespread in bacteria, although only a few classes have been discovered overall. Also, although traditional, signal-responsive riboswitches have not yet been discovered to promote PA, it is increasingly clear that small RNA elements are still oftentimes required. In some instances, small RNA elements serve as loading sites for cellular factors that promote PA. In other instances, larger, more complicated RNA elements participate in PA in unknown ways, perhaps even acting alone to trigger PA activity. These discoveries suggest that what is now needed is a systematic exploration of PA in bacteria, to determine how broadly these transcription elongation mechanisms are utilized, to reveal the diversity in their molecular mechanisms, and to understand the general logic behind their cellular applications. This review covers the known examples of PA regulatory mechanisms and speculates that they may be broadly important to bacteria.

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Figures

Image of FIGURE 1
FIGURE 1

Genomic context of PA systems. This figure schematically illustrates the transcripts regulated by the λN, , rRNA, and EAR RNA-based antitermination systems. (A) Phage λ early transcripts are initiated from two divergently facing promoters with elements found early in the transcripts. The λN protein is encoded by the first gene in the left early transcript. RNAP complexes associated with λN bypass multiple terminators in both transcripts. Using a different mechanism, the λQ protein promotes antitermination of the late transcript by binding to DNA near the late promoter and promoting a terminator-resistant configuration of RNAP. (B) Phage HK022 early transcripts are similar to phage λ, although they include elements early in each transcript, which trigger λN-independent antitermination. Additional Rho-dependent terminators are likely present in these transcripts, although they have not been specifically characterized and are therefore not indicated here. (C) A representative rRNA operon is shown, containing elements immediately downstream of the P promoter. These elements promote read-through of Rho-dependent termination in the noncoding rRNA genes. (D) Several intrinsic terminators have been demonstrated in the operon, which codes for biosynthesis of biofilm exopolysaccharides. The -associated RNA (EAR) is found within the intergenic region and promotes read-through of the terminators within the operon. Intrinsic terminators are shown as sticks with empty circles, and Rho termination regions are shown as sticks with wavy lines, both in red. RNA elements involved in antitermination are shown in blue, and proteins and protein-coding genes involved in antitermination are shown in green. Elements are not shown to scale.

Source: microbiolspec September 2018 vol. 6 no. 5 doi:10.1128/microbiolspec.RWR-0031-2018
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Image of FIGURE 2
FIGURE 2

Cryo-EM reveals details of the antitermination mechanism. This figure contains structural models generated from cryo-EM data on TECs (PDB IDs: 5MS0 and 6FLQ). (A) The λN antitermination complex (PDB ID: 5MS0) comprising λN (black), NusA (magenta), NusB (red), S10 (orange), NusG (green), and RNA (blue), in addition to RNAP (gray). (B) A zoom-in on the and λN complex shows extended binding of the RNA sequence with multiple protein components, with bound to the NusB-S10 dimer and the hairpin bound to λN and NusA. (C) Formation of the λN antitermination complex shifts the position of NusA (magenta) by 40° away from the RNA exit channel, as compared to NusA (purple) in a TEC constructed with the hairpin-mediated pause sequence (PDB ID: 6FLQ). Nascent RNA is shown in green.

Source: microbiolspec September 2018 vol. 6 no. 5 doi:10.1128/microbiolspec.RWR-0031-2018
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Image of FIGURE 3
FIGURE 3

RNA elements involved in PA. This figure shows the sequence and secondary structure of RNA elements known or predicted to be utilized in PA mechanisms. Shown are the and elements forming the λN sequence as well as rRNA antitermination signal, the RNA element from phage HK022, EAR from the exopolysaccharide pathway, and a UNCG-type hairpin implicated in LoaP antitermination.

Source: microbiolspec September 2018 vol. 6 no. 5 doi:10.1128/microbiolspec.RWR-0031-2018
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Image of FIGURE 4
FIGURE 4

Genomic context of NusG paralog antitermination systems. This figure illustrates the transcripts regulated by the RfaH, LoaP, and UpxY antitermination systems. (A) RfaH regulates multiple pathways in , including the hemolysin, F pilus, and lipo- and exopolysaccharide operons. Each regulated transcript includes the DNA element for RfaH recruitment. RfaH promotes antitermination of Rho-dependent promoters. (B) LoaP regulates two polyketide antibiotic operons in : the difficidin operon and the macrolactin operon. LoaP is found divergently oriented upstream of the operon. Each transcript includes a required sequence region in the 5′ leader region, which might include a functionally important hairpin followed by an intrinsic terminator. Additional intrinsic terminator sites have been implicated within the and operons, although they are not shown in this figure. (C) UpxY proteins regulate multiple capsular polysaccharide pathways in . Each polysaccharide operon includes both a UpxY and UpxZ protein involved in targeted regulation, with the 5′ leader sequence required for antitermination. has eight distinct polysaccharide operons containing UpxY proteins. Gray rectangles represent multigene operons. RNA elements potentially involved in antitermination are shown in blue, and proteins and protein-coding genes involved in antitermination are shown in green.

Source: microbiolspec September 2018 vol. 6 no. 5 doi:10.1128/microbiolspec.RWR-0031-2018
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Image of FIGURE 5
FIGURE 5

The RfaH CTD undergoes a large conformational shift from an α-helix to a β-barrel. Full-length RfaH (left) exists as an autoinhibited structure with the CTD (blue) in an α-helix conformation bound to the NTD (red) (PDB ID: 2OUG). Upon binding to RNAP and the DNA, the CTD (right) is released and forms the β-barrel conformation characteristic of NusG KOW domains (PDB ID: 2LCL).

Source: microbiolspec September 2018 vol. 6 no. 5 doi:10.1128/microbiolspec.RWR-0031-2018
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Image of FIGURE 6
FIGURE 6

Phylogenetic tree of NusG, Spt5, and specialized NusG paralog groups. Represented NusG sequences selected from the subgroups discussed in this review form the NusG family. Bacterial sequences from core NusG proteins are found in all bacteria, while a variety of paralogs are found in diverse bacteria phyla. Some groups of NusG paralogs are commonly found in or adjacent to large gene clusters coding for production of polysaccharides (PS) or polyketides (PK).

Source: microbiolspec September 2018 vol. 6 no. 5 doi:10.1128/microbiolspec.RWR-0031-2018
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