Bacteriophage T4 DNA Topoisomerase is the Target of Antitumor Agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia Coli

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1989 Feb 1

PMID 2537494

Citations 11

Authors

A C Huff

J K Leatherwood

K N Kreuzer

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Bacteriophage T4 genome.

Miller E, Kutter E, Mosig G, Arisaka F, Kunisawa T, Ruger W Microbiol Mol Biol Rev. 2003; 67(1):86-156, table of contents.

PMID: 12626685 PMC: 150520. DOI: 10.1128/MMBR.67.1.86-156.2003.

An antitumor drug-induced topoisomerase cleavage complex blocks a bacteriophage T4 replication fork in vivo.

Hong G, Kreuzer K Mol Cell Biol. 1999; 20(2):594-603.

PMID: 10611238 PMC: 85141. DOI: 10.1128/MCB.20.2.594-603.2000.

Characterization of DNA topoisomerase activity in two strains of Mycoplasma fermentans and in Mycoplasma pirum.

Horowitz S, Maor R, Priel E J Bacteriol. 1997; 179(21):6626-32.

PMID: 9352909 PMC: 179588. DOI: 10.1128/jb.179.21.6626-6632.1997.

Bacteriophage T4 mutants hypersensitive to an antitumor agent that induces topoisomerase-DNA cleavage complexes.

Woodworth D, Kreuzer K Genetics. 1996; 143(3):1081-90.

PMID: 8807283 PMC: 1207380. DOI: 10.1093/genetics/143.3.1081.

Mutational analysis of a type II topoisomerase cleavage site: distinct requirements for enzyme and inhibitors.

Freudenreich C, Kreuzer K EMBO J. 1993; 12(5):2085-97.

PMID: 8387918 PMC: 413430. DOI: 10.1002/j.1460-2075.1993.tb05857.x.

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