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The tmRNA‐tagging mechanism and the control of gene expression: a review

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Abstract The tmRNA‐mediated trans‐translation system is a unique quality control system in eubacteria that combines translational surveillance with the rescue of stalled ribosomes. During trans‐translation, the chimeric tmRNA molecule—which acts as both tRNA and mRNA—is delivered to the ribosomal A site by a ribonucleoprotein complex of SmpB and EF‐Tu–GTP, allowing the stalled ribosome to switch template and resume translation on a small coding sequence inside the tmRNA molecule. As a result, the aberrant protein becomes tagged by a sequence that is a target for proteolytic degradation. Thus, the system elegantly combines ribosome recycling with a clean‐up function when triggered by truncated transcripts or rare codons. In addition, recent observations point to a specific regulation of the translation of a small number of genes by tmRNA‐mediated inhibition or stimulation. In this review, we discuss the most prominent biochemical and structural aspects of trans‐translation and then focus on the specific role of tmRNA in stress management and cell‐cycle control of morphologically complex bacteria. WIREs RNA 2011 2 233–246 DOI: 10.1002/wrna.48 This article is categorized under: Translation > Translation Mechanisms Translation > Translation Regulation RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

The tmRNA‐tagging mechanism. By virtue of the trans‐translation mechanism's duality (ribosome release and protein tagging) nonfinished proteins become cotranslationally marked for destruction. The red line is the end of the reading frame of tmRNA, and represents the stop codon, to be recognized by the release factor (RF). For further explanation see text.

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tmRNA tagging controls misfolded protein levels. Upon stress, tmRNA (1) and, via RpoH, dnaK levels (2) are increased.88,107,108 In turn, tmRNA stimulates DnaK translation (3)65 and frees stalled ribosomes (5).8 Misfolded proteins may force ribosome stalling,42 and DnaK aids in the cotranslational (re‐)folding of nascent peptide chains, allowing the process to continue normally (4).

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Scanning electron micrographs demonstrating the sporulation defect of the ssrA mutant of S. coelicolor. Top row, wild‐type strain M145; Bottom row, ssrA mutant. Note that many aerial hyphae of the ssrA mutant produce branches, which is never seen in wild‐type hyphae. Inset: rare example of a spore chain.

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Colony morphology of ssrA mutants (ΔssrA) of S. coelicolor M145 and complementation by ssrA in trans. Deletion of ssrA leads to strongly reduced growth rate and colony size, and while trans‐translation is restored by the introduction of both wild‐type ssrA and recombinant ssrA‐His, growth rate is not. However, sporulation (visible as gray pigmentation) is restored. Transformants: pHJL401, control plasmid without ssrA; ssrA‐wt, pHJL401 harboring wild‐type ssrA; ssrA‐His, pHJL401 harboring recombinant ssrA specifying tmRNA‐His. Images were taken by stereo microscopy, and shown at two magnifications as indicated by the mm bars.

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Structure of tmRNA (10Sa RNA) from E. coli (363 nt). The TLS is given in purple, the pseudoknot structures PK1‐4 in orange, cyan, red, and blue, respectively. Helix H2 (with section H2a, also called P2a) is the connection between the tRNA‐ and mRNA‐like domains of tmRNA. The tag sequence with underlined resume and stop codon encodes the amino acid sequence ANDENYALAA.

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Trend of the number of publications (blue bars) and citations (light blue zig‐zag line) of papers on tmRNA and trans‐translation. Note that it took 10 years since the first publication in 19791 before the publications truly took off. Search terms were ‘tmRNA’, ‘ssrA’ or ‘10Sa’. Data based on ISI Web of Science (year 2010 is not included).

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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
Translation > Translation Mechanisms
Translation > Translation Regulation

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