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Selective mRNA degradation by antisense oligonucleotide-2,5A chimeras: involvement of RNase H and RNase L.

Authors
  • Robbins, I
  • Mitta, G
  • Vichier-Guerre, S
  • Sobol, R
  • Ubysz, A
  • Rayner, B
  • Lebleu, B
Type
Published Article
Journal
Biochimie
Publisher
Elsevier
Publication Date
Jan 01, 1998
Volume
80
Issue
8-9
Pages
711–720
Identifiers
PMID: 9865493
Source
Medline
License
Unknown

Abstract

Antisense oligonucleotides (ON) allow the specific control of gene expression and phosphorothioate derivatives are currently being evaluated for possible clinical applications. Numerous second generation ON analogues with improved pharmacological properties have been described. Most of them, however, do not recruit RNase H, which is known to increase ON potency by eliciting the specific degradation of the target RNA. Silverman, Torrence and colleagues have conjugated 2,5A to natural antisense ON and demonstrated the preferential cleavage of a target RNA in cell-free and intact cell experiments. We have established for the first time that RNase H-incompetent ON, viz. alpha-anomeric ON analogues, can be converted into sequence-specific nucleases upon conjugation to 2,5A. The use of alpha-ON- and beta-ON-2,5A chimeras has allowed us to delineate the part played by RNase H and RNase L in target RNA degradation and translation arrest. Finally, the present studies have revealed limitations which are encountered in the choice of a suitable target for such ON-2,5A chimeras.

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