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Bacteriophage T4 DNA topoisomerase is the target of antitumor agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia coli.

Publication ,  Journal Article
Huff, AC; Leatherwood, JK; Kreuzer, KN
Published in: Proc Natl Acad Sci U S A
February 1989

The mammalian type II DNA topoisomerase has been proposed to be the intracellular target of a variety of antitumor agents, including m-AMSA [4'-(9-acridinylamino)-methanesulfon-m-anisidide]. Because the bacteriophage T4-encoded topoisomerase resembles the mammalian enzyme, we are using T4 as a simple model system to investigate the mechanism of action of m-AMSA. A mutation that renders T4 growth m-AMSA-resistant is closely linked to an amber mutation in T4 gene 39, which encodes one of the topoisomerase subunits. In addition, the gene 39 subunit from the m-AMSA-resistant mutant phage has an altered net charge, strongly indicating that the drug-resistance mutation is within gene 39. Topoisomerase purified from mutant phage-infected Escherichia coli exhibits drug-insensitive DNA relaxation and DNA cleavage activities. Because a single mutation results in both drug-resistant phage growth and a drug-insensitive viral topoisomerase, we conclude that the T4-encoded type II DNA topoisomerase is the physiological target of m-AMSA in phage-infected E. coli.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 1989

Volume

86

Issue

4

Start / End Page

1307 / 1311

Location

United States

Related Subject Headings

  • T-Phages
  • Mutation
  • Genes, Viral
  • Genes
  • Escherichia coli
  • Drug Resistance, Microbial
  • DNA Topoisomerases, Type II
  • Amsacrine
 

Citation

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Huff, A. C., Leatherwood, J. K., & Kreuzer, K. N. (1989). Bacteriophage T4 DNA topoisomerase is the target of antitumor agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia coli. Proc Natl Acad Sci U S A, 86(4), 1307–1311. https://doi.org/10.1073/pnas.86.4.1307
Huff, A. C., J. K. Leatherwood, and K. N. Kreuzer. “Bacteriophage T4 DNA topoisomerase is the target of antitumor agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia coli.Proc Natl Acad Sci U S A 86, no. 4 (February 1989): 1307–11. https://doi.org/10.1073/pnas.86.4.1307.
Huff, A. C., et al. “Bacteriophage T4 DNA topoisomerase is the target of antitumor agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia coli.Proc Natl Acad Sci U S A, vol. 86, no. 4, Feb. 1989, pp. 1307–11. Pubmed, doi:10.1073/pnas.86.4.1307.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

February 1989

Volume

86

Issue

4

Start / End Page

1307 / 1311

Location

United States

Related Subject Headings

  • T-Phages
  • Mutation
  • Genes, Viral
  • Genes
  • Escherichia coli
  • Drug Resistance, Microbial
  • DNA Topoisomerases, Type II
  • Amsacrine