Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
POLYNUCLEOTIDE RECOGNITION AND STRAND SCISSION BY BLEOMYCIN AND RIBONUCLEASE P
Diss Abstr Int [B]; 51(5):2328 1990. Unique Identifier : AIDSLINE ICDB/91669629 Carter BJ; Univ. of Virginia
Abstract:
Processing of a synthetic tRNA(Phe) dimer and a natural mutant tRNA(His) precursor by RNase P occurred at two different sites, depending upon experimental conditions. The alternate site for both substrates was induced only by high concentrations of Mg++, and was determined to occur one base 5'- to the normal site. Bleomycin-mediated cleavage of several RNA substrates was investigated. A B. subtilis tRNA(His) precursor molecule was found to be an excellent substrate for Fe(II).BLM A2, but an E coli tRNA(Tyr) precursor molecule was found to be a very poor substrate for BLM A2. BLM cleavage of RNA was found to be highly selective compared to DNA cleavage. A 231-nucleotide RNA transcript from the E coli pSP64 plasmid vector was also a very good substrate for BLM cleavage, having two strong BLM cleavage sites. A 322-base fragment of the HIV reverse transcriptase mRNA molecule, another good substrate for BLM cleavage, had two strong cleavage sites, and two other lesser sites. The discovery that some RNA molecules are substrates for highly selective cleavage by BLM challenges the belief that DNA cleavage is the locus of action for BLM's antitumor activity. We propose that the true therapeutic target for BLM may actually be RNA, and the source of BLM's antitumor specificity may be related to its highly selective cleavage of certain critical RNA molecules. Four glycine-substituted analogs of deglyco bleomycin (BLM) demethyl A2 were tested for DNA cleavage activity and specificity. These glycine analogs had the threonine peptide linkage of BLM replaced by either 0, 1, 2, or 4 glycine moieties. These variable length gly(x)-BLM demethyl A2 analogs were investigated to help elucidate which region of BLM is responsible for the extensive DNA cleavage specificity exhibited by BLM. None of the gly(x)-BLM analogs exhibited any change in cleavage specificity for a 5'-32P-end labeled 242-bp restriction fragment of SV40 DNA containing an isolated BLM cleavage site. The lack of any change in specificity for the gly(x)-BLM analogs indicates that the metal binding region of BLM is primarily responsible both for cleavage and cleavage specificity. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD90-24673)
Keywords: *Antineoplastic Agents Bacillus subtilis/METABOLISM Bleomycin/METABOLISM/*PHARMACOLOGY DNA/*DRUG EFFECTS/METABOLISM Endoribonucleases/*METABOLISM Escherichia coli/METABOLISM RNA/*DRUG EFFECTS/METABOLISM RNA, Bacterial/DRUG EFFECTS/METABOLISM RNA, Transfer, His/DRUG EFFECTS/METABOLISM RNA, Transfer, Tyr/DRUG EFFECTS/METABOLISM Structure-Activity Relationship Substrate Specificity THESIS 910430
M9140681
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Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
