Site-specific cleavage of RNA by Fe(II)·bleomycin

Barbara J. Carter, Erik De Vroom, Eric C. Long, Gijs A. Van Der Marel, Jacques H. Van Boom, Sidney M. Hecht

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

Bleomycin is an antitumor agent whose activity (us long been thought to derive from its ability to degrade DNA. Recent findings suggest that cellular RNA may be a therapeutically relevant locus. At micromolar concentrations, Fe(II)-bleomycin readily cleaved a Bacillus subtilis tRNAHis incursor in a highly selective fashion, but Escherichia coli tRNATyr precursor was largely unaffected even under more forcing conditions. Other substrates included an RNA transcript encoding a large segment of the reverse transcriptase from human immunodeficiency virus 1. RNA cleavage was oxidative, ≈ 10-fold more selective than DNA cleavage, and largely unaffected by nonsubstrate RNAs. RNA sequence analysis suggested recognition of RNA tertiary structure, rather than recognition of specific sequences; subsets of nucleotides at the junction of single- and double-stranded regions were especially susceptible to cleavage. The ready accessibility of cellular RNAs to xenobiotic agents, the high selectivity of bleomycin action on RNAs, and the paucity of mechanisms for RNA repair suggest that RNA may be a therapeutically relevant target for bleomycin.

Original languageEnglish (US)
Pages (from-to)9373-9377
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume87
Issue number23
DOIs
StatePublished - Jan 1 1990

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Keywords

  • Antitumor antibiotic
  • Human immunodeficiency virus reverse transcriptase mRNA
  • Mechanism of action
  • Oxidative degradation
  • TRNA precursors

ASJC Scopus subject areas

  • General

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