Chapter category: RNA

Cleavage of RNA by Fe(II)-Bleomycin

This chapter appears in the following book:

RNA-Binding Antibiotics

Edited by: Renee Schroeder
ISBN: 1-58706-012-4
» Get more information about this book at landesbioscience.com «

Chapter authors:
Pradip Mascharak and Alexander Hüttenhofer

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Clinical success of the bleomycin family of glycopeptide antibiotics in combination chemotherapy against several types of cancer^1-3 is believed to be related to their ability to bind to cellular DNA and inflict strand breaks in the presence of metal ions and dioxygen.^4,5 Rapid in vitro DNA strand scission reaction by bleomycin is easily noticed in the presence of Fe(II) and dioxygen. It is believed that the Fe²⁺ ion binds to the pyrimidineb aminoalaninamide_hydroxyhistidine portion of the drug (boxed area in Fig. 1) and the metallodrug associates with cellular DNA via intercalation of the bithiazole moiety into the base stack as well as electrostatic interaction between the positivelycharged amine tail and the polyphosphate backbone. Oxygenation of the Fe(II)bleomycin complex results in the formation of highlyoxidizing ironoxo species which cause strand scission via damage to the nearby deoxyribose rings. The Fe(II)bleomycininduced DNA cleavage is sequence specific and breaks are observed immediately following 5'GC3' and 5'GT3' sequences. Both free bases and malondialdehydelike material (base propenals) are obtained as products of the DNA degradation. Recent studies have also shown that Fe(II)bleomycin complex can bind to and cleave specific RNAs, RNA precursors, and RNADNA hybrids.⁶ Although the binding of metallobleomycins to DNA has been studied by physical techniques,^7,8 the results could not be directly extended to the area of RNA since the more irregular secondary and tertiary structure of RNA complicates the process of binding of Fe(II)bleomycin to RNA, particularly in the presence of other physiologically important metal ions. In this account, we examine the mode of binding of Fe(II)bleomycin to RNA and comment on the relationship between the RNA cleavage activity of Fe(II)bleomycin and the clinical cytotoxicity of the drug.

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Chapter category: RNA

Cleavage of RNA by Fe(II)-Bleomycin

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