Neomycin B inhibits splicing of the td intron indirectly by interfering with translation and enhances missplicing in vivo.

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Neomycin B inhibits splicing of the td intron indirectly by interfering with translation and enhances missplicing in vivo.

RNA. 1998 Dec;4(12):1653-63. Unique Identifier : AIDSLINE MED/99063406
Waldsich C; Semrad K; Schroeder R; Institute of Microbiology and Genetics, University of Vienna,; Austria.

Abstract: The aminoglycoside antibiotic neomycin B inhibits translation in prokaryotes and interferes with RNA-protein interactions in HIV both in vivo and in vitro. Hitherto, inhibition of ribozyme catalysis has only been observed in vitro. We therefore monitored the activity of neomycin B and several other aminoglycoside antibiotics on splicing of the T4 phage thymidylate synthase (td) intron in vivo. All antibiotics tested inhibited splicing, even chloramphenicol, which does not inhibit splicing in vitro. Splicing of the td intron in vivo requires translation for proper folding of the pre-mRNA. In the absence of translation, two interactions between sequences in the upstream exon and the 5' and 3' splice sites trap the pre-mRNA in splicing-incompetent conformations. Their disruption by mutations rendered splicing less dependent on translation and also less sensitive to neomycin B. Intron splicing was affected by neither neomycin B nor gentamicin in Escherichia coli strains carrying antibiotic-resistance genes that modify the ribosomal RNA. Taken together, this demonstrates that in vivo splicing of td intron is not directly inhibited by aminoglycosides, but rather indirectly by their interference with translation. This was further confirmed by assaying splicing of the Tetrahymena group I intron, which is inserted in the E. coli 23 S rRNA and, thus, not translated. Furthermore, neomycin B, paromomycin, and streptomycin enhanced missplicing in antibiotic-sensitive strains. Missplicing is caused by an alternative structural element containing a cryptic 5' splice site, which serves as a substrate for the ribozyme. Our results demonstrate that aminoglycoside antibiotics display different effects on ribozymes in vivo and in vitro.

Keywords: JOURNAL ARTICLE Animal Base Sequence Chloramphenicol/PHARMACOLOGY Drug Resistance, Microbial/GENETICS DNA Primers Exons Framycetin/*PHARMACOLOGY Gentamicins/PHARMACOLOGY *Introns RNA Splicing/*DRUG EFFECTS Streptomycin/PHARMACOLOGY Support, Non-U.S. Gov't Tetrahymena thermophila/GENETICS Translation, Genetic/*DRUG EFFECTS
990330
A9931101

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