Efficient improvement of hammerhead ribozyme mediated cleavage of long substrates by oligonucleotide facilitators

Biochemistry
E Jankowsky, B Schwenzer

Abstract

Hammerhead ribozymes were found to be not very efficient in cleaving long RNA substrates in trans. Oligonucleotide facilitators, capable of affecting hammerhead ribozymes by interacting with the substrate at the termini of the ribozyme, may improve this reaction. We determined in vitro the effects of 18 DNA and RNA oligonucleotide facilitators on three substrates containing 39, 452, and 942 nucleotides, respectively, by estimating the facilitator influences on association between ribozyme and substrate and on the cleavage step. The effects increase with the length of the substrates. With the 39mer substrate a maximal 4-fold enhancement of the ribozyme activity could be detected, the reaction with the 942mer substrate was accelerated up to 115-fold by facilitator addition. In long, structured substrates the facilitators have the potential to preform the substrate for the ribozyme attack. Due to this preforming effect, the rate of ribozyme-substrate association was increased as well as the rate of the cleavage step. 3'-End facilitators accelerate both of these rates, largely independent on the facilitator length. The rate of the cleavage step is raised as a result of a favorable activation energy gain by these facilitators. With ...Continue Reading

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Citations

Aug 13, 2005·Journal of Molecular Evolution·Kevin E NelsonYi Lu
Jan 7, 1998·Bioorganic & Medicinal Chemistry·F BurlinaJ L Fourrey
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