Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks

Author:

Avemann K1,Knippers R1,Koller T1,Sogo J M1

Affiliation:

1. Fakultät für Biologie, Universität Konstanz, Federal Republic of Germany.

Abstract

The structure of replicating simian virus 40 minichromosomes, extracted from camptothecin-treated infected cells, was investigated by biochemical and electron microscopic methods. We found that camptothecin frequently induced breaks at replication forks close to the replicative growth points. Replication branches were disrupted at about equal frequencies at the leading and the lagging strand sides of the fork. Since camptothecin is known to be a specific inhibitor of type I DNA topoisomerase, we suggest that this enzyme is acting very near the replication forks. This conclusion was supported by experiments with aphidicolin, a drug that blocks replicative fork movement, but did not prevent the camptothecin-induced breakage of replication forks. The drug teniposide, an inhibitor of type II DNA topoisomerase, had only minor effects on the structure of these replicative intermediates.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

Reference37 articles.

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3. A high affinity topoisomerase I binding sequence is clustered at DNase I hypersensitive sites in tetrahymena R-chromatin;Bonven B. J.;Cell,1985

4. Camptothecin inhibits macromolecular synthesis in mammalian cells but not in isolated mitochondria or E. coli;Bosmann H. B.;Biochem. Biophys. Res. Commun.,1970

5. Need for DNA topoisomerase activity as a swivel for DNA replication and for transcription of ribosomal RNA;Brill S. J.;Nature (London),1987

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