Degradation of Structurally Modified DNAs by Bleomycin Group Antibiotics

Robert P. Hertzberg, Mary Jo Caranfa, Sidney M. Hecht

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Bleomycin-mediated DNA strand scission has been shown to be diminished at certain sequences in proximity to 5-methylcytidines. We have investigated the molecular basis of this observed diminution using selective bleomycin (BLM) modifications at the C-terminus. of the four different bleomycin congeners investigated, only bleomycin A2and bleomycin BAPP were substantially affected by cytidine methylation. We have also examined the effect of other DNA modifications on bleomycin-mediated strand scission. Methylation at the N6position of adenosine resulted in diminution of DNA cleavage by all four bleomycin congeners. The presence of bulky 5-(glucosyloxy)methyl groups in the major groove of T4 DNA had little effect on the efficiency of DNA strand scission mediated by bleomycin A2or B2, suggesting the absence of important steric interactions between Fe(II).BLM and DNA in the major groove. In contrast, DNA cleavage mediated by bleomycin congeners was very sensitive to a major DNA conformational change, the B → Z transition. Salt and MgCl2titrations of the DNA copolymers poly(dG-dC).poly(dG-dC) and poly(dG-MedC)«poly(dG-McdC) demonstrated that bleomycin A2and B2did not cleave Z-DNA efficiently. In addition, circular dichroism titrations of these copolymers revealed that both bleomycin congeners increased the cation concentration necessary to induce the B→Z transition, implying that bleomycin preferentially binds to and stabilizes B-form DNA. These results are consistent with a model in which cytidine methylation at appropriate sequences of DNA is sufficient to induce subtle conformational changes that render the helix unreceptive to cleavage by some bleomycin congeners.

Original languageEnglish (US)
Pages (from-to)3164-3174
Number of pages11
JournalBiochemistry
Volume27
Issue number9
DOIs
StatePublished - May 1 1988
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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