Genome-wide effects of the antimicrobial peptide apidaecin on translation termination

Mangano, Kyle; Florin, Tanja; Shao, Xiaofeng; Klepacki, Dorota; Chelysheva, Irina; Ignatova, Zoya; Gao, Yu; Mankin, Alexander S.; Vázquez‐Laslop, Nora

doi:10.1101/2020.05.17.100735

Cited by 2 publications

(1 citation statement)

References 69 publications

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“…In both cases, we found evidence of translational stress in the forms of idle ribosomes at the corresponding stop codons and queuing upstream (Fig. 4a), similar to what was previously observed under different translation termination stresses (Baggett et al, 2017;Mangano et al, 2020;Saito et al, 2020). Specifically, we observed queues at UAG stops under RF1/PrmC depletion, queues at UGA stops under RF2 depletion, and no queues in wild-type, or at UAA stops in either depletion.…”

Section: Activation Of Regulator B Does Not Results From General Stressupporting

confidence: 86%

Spurious regulatory connections dictate the expression-fitness landscape of translation termination factors

Lalanne

Parker

2020

Preprint

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During steady-state cell growth, individual enzymatic fluxes can be directly inferred from growth rate by mass conservation, but the inverse problem remains unsolved. Perturbing the flux and expression of a single enzyme could have pleiotropic effects that may or may not dominate the impact on cell fitness. Here we quantitatively dissect the molecular and global responses to varied expression of translation termination factors (peptide release factors, RFs) in bacterium Bacillus subtilis. While endogenous RF expression maximizes proliferation, deviations in expression lead to unexpected distal regulatory responses that dictate fitness reduction. Molecularly, RF depletion causes expression imbalance at specific operons, which activates master regulators and detrimentally overrides the transcriptome. Through these spurious connections, RF abundances are thus entrenched by focal points within the regulatory network, in one case located at a single stop codon. Such regulatory entrenchment suggests that predictive bottom-up models of expression-fitness landscapes will require near-exhaustive characterization of parts.HighlightsPrecision measurements enable multiscale expression-to-fitness mapping.RF depletion leads to imbalanced translation for co-transcribed gene pairs.Imbalanced translation induces unintended regulons to the detriment of cell fitness.Swapping a single stop codon rewires global susceptibility to RF perturbation.

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Section: Activation Of Regulator B Does Not Results From General Stressupporting

confidence: 86%

Spurious regulatory connections dictate the expression-fitness landscape of translation termination factors

Lalanne

Parker

2020

Preprint

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Selective inhibition of human translation termination by a drug-like compound

Chang

Ward

et al. 2020

Nat Commun

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Methods to directly inhibit gene expression using small molecules hold promise for the development of new therapeutics targeting proteins that have evaded previous attempts at drug discovery. Among these, small molecules including the drug-like compound PF-06446846 (PF846) selectively inhibit the synthesis of specific proteins, by stalling translation elongation. These molecules also inhibit translation termination by an unknown mechanism. Using cryo-electron microscopy (cryo-EM) and biochemical approaches, we show that PF846 inhibits translation termination by arresting the nascent chain (NC) in the ribosome exit tunnel. The arrested NC adopts a compact α-helical conformation that induces 28 S rRNA nucleotide rearrangements that suppress the peptidyl transferase center (PTC) catalytic activity stimulated by eukaryotic release factor 1 (eRF1). These data support a mechanism of action for a small molecule targeting translation that suppresses peptidyl-tRNA hydrolysis promoted by eRF1, revealing principles of eukaryotic translation termination and laying the foundation for new therapeutic strategies.

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Genome-wide effects of the antimicrobial peptide apidaecin on translation termination

Cited by 2 publications

References 69 publications

Spurious regulatory connections dictate the expression-fitness landscape of translation termination factors

Spurious regulatory connections dictate the expression-fitness landscape of translation termination factors

Selective inhibition of human translation termination by a drug-like compound

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