TAILIEUCHUNG - Báo cáo Y học: Inhibition of nuclear pre-mRNA splicing by antibiotics in vitro

A number of antibiotics have been reported to disturb the decoding process in prokaryotic translation and to inhibit the function of various natural ribozymes. We investigated the e ect of several antibiotics on in vitro splicing of a eukaryotic nuclear pre-mRNA (b-globin). Of the eight antibiotics studied, erythromycin, Cl-tetracycline and streptomycinwere identi®ed as splicing inhibitors in nuclear HeLa cell extract. TheKi values were 160, 180 and 230lM, respectively. | Eur. J. Biochem. 269 175-183 2002 FEBS 2002 Inhibition of nuclear pre-mRNA splicing by antibiotics in vitro Maren Hertweck Reinhard Hiller and Manfred W. Mueller Vienna BioCenter Institute of Microbiology and Genetics Vienna Austria A number of antibiotics have been reported to disturb the decoding process in prokaryotic translation and to inhibit the function of various natural ribozymes. We investigated the effect of several antibiotics on in vitro splicing of a eukaryotic nuclear pre-mRNA b-globin . Of the eight antibiotics studied erythromycin Cl-tetracycline and streptomycin were identified as splicing inhibitors in nuclear HeLa cell extract. The Ki values were 160 180 and 230 M respectively. Cl-tetracycline-mediated and streptomycin-mediated splicing inhibition were in the molar inhibition range for hammerhead and human hepatitis delta virus ribozyme self-cleavage tetracycline of group-I intron selfsplicing streptomycin and inhibition of RNase P cleavage by some aminoglycosides. Cl-tetracycline and the aminocyclitol glycoside streptomycin were found to have an indirect effect on splicing by unspecific binding to the pre-mRNA suggesting that the inhibition is the result of disturbance of the correct folding of the pre-mRNA into the splicing-compatible tertiary structure by the charged groups of these antibiotics. The macrolide erythromycin the strongest inhibitor had only a slight effect on formation of the presplicing complexes A and B but almost completely inhibited formation of the splicing-active C complex by binding to nuclear extract component s . This results in direct inhibition of the second step of pre-mRNA splicing. To our knowledge this is the frst report on specifc inhibition of nuclear splicing by an antibiotic. The functional groups involved in the interaction of erythromycin with snRNAs and or splicing factors require further investigation. Keywords erythromycin Cl-tetracycline nuclear splicing inhibition spliceosomal complex C. Recognition of

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