Bacterial addiction module toxin Doc inhibits translation elongation through its association with the 30S ribosomal subunit

Liu, Mohan; Zhang, Yonglong; Inouye, Masayori; Woychik, Nancy A.

doi:10.1073/pnas.0711949105

Cited by 119 publications

(105 citation statements)

References 55 publications

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“…Doc Induces RelE-mediated Cleavage of Model mRNAs-A recent study showed that Doc expression in E. coli strain BL21(DE3) led to mRNA stabilization (13). By contrast, we observe destabilization of two different model mRNAs (lpp and dksA) after induction of doc in E. coli strain MG1655 (Fig.…”

Section: Doc Induces Growth Arrest But Not Cell Death-induction Of Domentioning

confidence: 58%

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Doc of Prophage P1 Is Inhibited by Its Antitoxin Partner Phd through Fold Complementation

García-Pino

Christensen-Dalsgaard

Wyns

et al. 2008

Journal of Biological Chemistry

108

122

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Prokaryotic toxin-antitoxin modules are involved in major physiological events set in motion under stress conditions. The toxin Doc (death on curing) from the phd/doc module on phage P1 hosts the C-terminal domain of its antitoxin partner Phd (prevents host death) through fold complementation. This Phd domain is intrinsically disordered in solution and folds into an ␣-helix upon binding to Doc. The details of the interactions reveal the molecular basis for the inhibitory action of the antitoxin. The complex resembles the Fic (filamentation induced by cAMP) proteins and suggests a possible evolutionary origin for the phd/doc operon. Doc induces growth arrest of Escherichia coli cells in a reversible manner, by targeting the protein synthesis machinery. Moreover, Doc activates the endogenous E. coli RelE mRNA interferase but does not require this or any other known chromosomal toxin-antitoxin locus for its action in vivo.Small operons encoding a toxin and its antitoxin are common in the genomes of bacteria and archaea and are also found on certain plasmids and bacteriophages. These so-called toxinantitoxin (TA) 2 modules have been proposed to regulate the pace of metabolism and may induce a state of dormancy in case of nutritional stress (1-3). TA modules are highly abundant in opportunistic pathogens such as Mycobacterium tuberculosis (4), and their presence has been linked to persistence (5).On plasmids, TA modules act as addiction systems, aiding plasmid maintenance in the bacterial population by post-segregational killing (6), filling in a function related to apoptosis and programmed cell death in eukaryotes (7). Related effects have been observed for chromosome-located TA systems as some of them have been shown to diminish large scale genome reductions in the absence of selection (8). In the presence of the plasmid, both toxin and antitoxin are expressed, leading to a steady state equilibrium where the antitoxin counteracts the effect of the toxin. In its free state, the antitoxin, usually a modular protein that contains a functional intrinsically disordered region (9 -11), is under constant proteolytic attack. The toxinantitoxin complex acts as an autorepressor for the TA operon, ensuring that only small amounts of the proteins are present in the cell. Upon plasmid loss, the antitoxin is degraded by a specific intracellular protease, releasing the toxin. Without the possibility of replenishing the antitoxin population, the toxin action becomes irreversible, resulting in cell death.The phd/doc operon encodes a TA module aiding the maintenance of the plasmid-prophage P1 in Escherichia coli (12). Doc is an inhibitor of translation elongation through its association with the 30 S ribosomal subunit in a way similar to the antibiotic hygromycin (13). The action of Doc is suppressed by the antitoxin Phd, which consists of two domains. Its C-terminal domain (residues 52-73) harbors the interaction site with Doc and on its own prevents Doc-mediated growth arrest (14,15). The N-terminal region (residues 1-51) of Phd i...

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Section: Doc Induces Growth Arrest But Not Cell Death-induction Of Domentioning

confidence: 58%

“…Doc is an inhibitor of translation elongation through its association with the 30 S ribosomal subunit in a way similar to the antibiotic hygromycin (13). The action of Doc is suppressed by the antitoxin Phd, which consists of two domains.…”

mentioning

confidence: 99%

Doc of Prophage P1 Is Inhibited by Its Antitoxin Partner Phd through Fold Complementation

García-Pino

Christensen-Dalsgaard

Wyns

et al. 2008

Journal of Biological Chemistry

108

122

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“…Doc P1 has been shown to interact with the 30S ribosomal subunit, and its toxicity is the result of inhibition of translation elongation, possibly at the translocation step (57). The Doc SI toxin shares 30% identity to Doc P1 , while the Phd SI is only distantly related to Phd P1 (17% identity), and they are even further less related to the Y. pestis proteins, 21% and Ͻ10%, respectively.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the phd-doc and ccd Toxin-Antitoxin Cassettes from Vibrio Superintegrons

et al. 2013

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c Toxin-antitoxin (TA) systems have been reported in the genomes of most bacterial species, and their role when located on the chromosome is still debated. TA systems are particularly abundant in the massive cassette arrays associated with chromosomal superintegrons (SI). Here, we describe the characterization of two superintegron cassettes encoding putative TA systems. The first is the phd-doc SI system identified in Vibrio cholerae N16961. We determined its distribution in 36 V. cholerae strains and among five V. metschnikovii strains. We show that this cassette, which is in position 72 of the V. cholerae N16961 cassette array, is functional, carries its own promoter, and is expressed from this location. Interestingly, the phd-doc SI system is unable to control its own expression, most likely due to the absence of any DNA-binding domain on the antitoxin. In addition, this SI system is able to cross talk with the canonical P1 phage system. The second cassette that we characterized is the ccd Vfi cassette found in the V. fischeri superintegron. We demonstrate that CcdB Vfi targets DNA-gyrase, as the canonical CcB F toxin, and that ccd Vfi regulates its expression in a fashion similar to the ccd F operon of the conjugative plasmid F. We also establish that this cassette is functional and expressed in its chromosomal context in V. fischeri CIP 103206T. We tested its functional interactions with the ccdAB F system and found that CcdA Vfi is specific for its associated CcdB Vfi and cannot prevent CcdB F toxicity. Based on these results, we discuss the possible biological functions of these TA systems in superintegrons.

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“…Reduced expression of the putative antitoxin homologues YefM and RelB also corroborates reduced cell growth. Both antitoxins participate in growth arrest and enable cell survival for prolonged times during environmental stresses (Liu et al, 2008). Antitoxins have been associated with cell persistence and are transcriptional repressors of toxin biosynthesis genes.…”

Section: Discussionmentioning

confidence: 99%

Physiology and transcriptome of the polycyclic aromatic hydrocarbon-degrading Sphingomonas sp. LH128 after long-term starvation

et al. 2013

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The survival, physiology and gene expression profile of the phenanthrene-degrading Sphingomonas sp. LH128 was examined after an extended period of complete nutrient starvation and compared with a non-starved population that had been harvested in exponential phase. After 6 months of starvation in an isotonic solution, only 5 % of the initial population formed culturable cells. Microscopic observation of GFP fluorescent cells, however, suggested that a larger fraction of cells (up to 80 %) were still alive and apparently had entered a viable but non-culturable (VBNC) state. The strain displayed several cellular and genetic adaptive strategies to survive longterm starvation. Flow cytometry, microscopic observation and fatty acid methyl ester (FAME) analysis showed a reduction in cell size, a change in cell shape and an increase in the degree of membrane fatty acid saturation. Transcriptome analysis showed decreased expression of genes involved in ribosomal protein biosynthesis, chromosomal replication, cell division and aromatic catabolism, increased expression of genes involved in regulation of gene expression and efflux systems, genetic translocations, and degradation of rRNA and fatty acids. Those phenotypic and transcriptomic changes were not observed after 4 h of starvation. Despite the starvation situation, the polycyclic aromatic hydrocarbon (PAH) catabolic activity was immediate upon exposure to phenanthrene. We conclude that a large fraction of cells maintain viability after an extended period of starvation apparently due to tuning the expression of a wide variety of cellular processes. Due to these survival attributes, bacteria of the genus Sphingomonas, like strain LH128, could be considered as suitable targets for use in remediation of nutrient-poor PAH-contaminated environments.

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Bacterial addiction module toxin Doc inhibits translation elongation through its association with the 30S ribosomal subunit

Cited by 119 publications

References 55 publications

Doc of Prophage P1 Is Inhibited by Its Antitoxin Partner Phd through Fold Complementation

Doc of Prophage P1 Is Inhibited by Its Antitoxin Partner Phd through Fold Complementation

Characterization of the phd-doc and ccd Toxin-Antitoxin Cassettes from Vibrio Superintegrons

Physiology and transcriptome of the polycyclic aromatic hydrocarbon-degrading Sphingomonas sp. LH128 after long-term starvation

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