Insights into functional modulation of catalytic RNA activity

Vourekas, Anastassios; Stamatopoulou, Vassiliki; Toumpeki, Chrisavgi; Tsitlaidou, Marianthi; Drainas, Denis

doi:10.1002/iub.105

Cited by 8 publications

(6 citation statements)

References 159 publications

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“…However, although the effect of binding to the ribosome is similar for all aminoglycosides, not all classes of these antimicrobials bind to identical sites of the 16S rRNA. Other effects that may or may not be secondary to RNA binding and protein mistranslation are inhibition of the 30S ribosomal subunit assembly (neomycin and paromomycin) [ 88 , 89 ], ribozyme-like activity resulting in cleavage of RNA molecules [ 90 , 91 , 92 ] or interference with essential functions dependent on ribozyme activity such inhibition of ribonuclease P [ 91 , 93 , 94 ].…”

Section: Mechanism Of Action and Side Effectsmentioning

confidence: 99%

Amikacin: Uses, Resistance, and Prospects for Inhibition

2017

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Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against these antibiotics is enzymatic modification by aminoglycoside-modifying enzymes that are divided into acetyl-transferases, phosphotransferases, and nucleotidyltransferases. To overcome this problem, new semisynthetic aminoglycosides were developed in the 70s. The most widely used semisynthetic aminoglycoside is amikacin, which is refractory to most aminoglycoside modifying enzymes. Amikacin was synthesized by acylation with the l-(−)-γ-amino-α-hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. The main amikacin resistance mechanism found in the clinics is acetylation by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib], an enzyme coded for by a gene found in integrons, transposons, plasmids, and chromosomes of Gram-negative bacteria. Numerous efforts are focused on finding strategies to neutralize the action of AAC(6′)-Ib and extend the useful life of amikacin. Small molecules as well as complexes ionophore-Zn+2 or Cu+2 were found to inhibit the acetylation reaction and induced phenotypic conversion to susceptibility in bacteria harboring the aac(6′)-Ib gene. A new semisynthetic aminoglycoside, plazomicin, is in advance stage of development and will contribute to renewed interest in this kind of antibiotics.

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Section: Mechanism Of Action and Side Effectsmentioning

confidence: 99%

Amikacin: Uses, Resistance, and Prospects for Inhibition

2017

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“…Ribozymes are RNA molecules that predominantly catalyze their own cleavage or that of other RNAs ( 136 , 137 ). They can generally be categorized into self-splicing group I/II introns, RNase P, self-cleaving regions of viral RNA, plant satellite RNAs and rRNA ( 101 ).…”

Section: Polyamine–rna Interactions At the Molecular Levelmentioning

confidence: 99%

Endogenous polyamine function—the RNA perspective

Lightfoot

Hall

2014

Nucleic Acids Research

117

107

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Recent progress with techniques for monitoring RNA structure in cells such as ‘DMS-Seq’ and ‘Structure-Seq’ suggests that a new era of RNA structure-function exploration is on the horizon. This will also include systematic investigation of the factors required for the structural integrity of RNA. In this context, much evidence accumulated over 50 years suggests that polyamines play important roles as modulators of RNA structure. Here, we summarize and discuss recent literature relating to the roles of these small endogenous molecules in RNA function. We have included studies directed at understanding the binding interactions of polyamines with polynucleotides, tRNA, rRNA, mRNA and ribozymes using chemical, biochemical and spectroscopic tools. In brief, polyamines bind RNA in a sequence-selective fashion and induce changes in RNA structure in context-dependent manners. In some cases the functional consequences of these interactions have been observed in cells. Most notably, polyamine-mediated effects on RNA are frequently distinct from those of divalent cations (i.e. Mg2+) confirming their roles as independent molecular entities which help drive RNA-mediated processes.

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“…22 The rRNA component of the ribosome is known to catalyze translation via its peptidyl transferase activity. 23, 24 Observation of the ribozyme-like properties in nc-rRNAs is very intriguing and supports that rRNA s and nc-rRNAs are highly reactive with diverse biological functions. Also, these nc-rRNAs and perhaps noncoding RNAs in other genes may require self-catalytic RNA processing before carrying out their putative functions.…”

Section: Discussionmentioning

confidence: 96%

Stabilization of ribozyme-like cis-noncoding rRNAs induces apoptotic and nonapoptotic death in lung cells

Fields

Shiao

2012

Cell Death Dis

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Bidirectional non-protein-coding RNAs are ubiquitously transcribed from the genome. Convergent sense and antisense transcripts may regulate each other. Here, we examined the convergent cis-noncoding rRNAs (nc-rRNAs) in A5 and E9 lung cancer models. Sense nc-rRNAs extending from rDNA intergenic region to internal transcribed spacer of around 10 kb in length were identified. nc-rRNAs in sense direction exhibited in vitro characteristics of ribozymes, namely, degradation upon incubation with MgCl2 and stabilization by complementary oligonucleotides. Detection of endogenous cleavage-ligation products carrying internal deletion of hundreds to thousands nucleotides by massively parallel sequencing confirmed the catalytic properties. Transfection of oligonucleotides pairing with antisense nc-rRNAs stabilized both target and complementary transcripts, perturbed rRNA biogenesis, and induced massive cell death via apoptotic and/or nonapoptotic mechanisms depending on cell type and treatment. Oligonucleotides targeting cellular sense transcripts are less responsive. Spontaneously detached cells, though rare, also showed accumulation of nc-rRNAs and perturbation of rRNA biogenesis. Direct participation of nc-rRNAs in apoptotic and nonapoptotic death was demonstrated by transfection of synthetic nc-rRNAs encompassing the rDNA promoter. In sum, convergent cis-nc-rRNAs follow a feed-forward mechanism to regulate each other and rRNA biogenesis. This opens an opportunity to disrupt rRNA biogenesis, commonly upregulated in cancers, via inhibition of ribozyme-like activities in nc-rRNAs.

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Insights into functional modulation of catalytic RNA activity

Cited by 8 publications

References 159 publications

Amikacin: Uses, Resistance, and Prospects for Inhibition

Amikacin: Uses, Resistance, and Prospects for Inhibition

Endogenous polyamine function—the RNA perspective

Stabilization of ribozyme-like cis-noncoding rRNAs induces apoptotic and nonapoptotic death in lung cells

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