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Interaction between Replication Forks and Topoisomerase I-DNA Cleavable Complexes: Studies in a Cell-free SV40 DNA Replication System¹

Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 [Y-P. T., L. F. L.]; Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205 [A. R.]; and Department of Medicine, New York University School of Medicine, New York, New York 10016 [G. N., R. S.]

The extreme S-phase-specific cytotoxicity of camptothecin has been shown to involve active DNA replication. To investigate the role of DNA replication in camptothecin cytotoxicity, we have studied the interaction between the DNA replication machinery and the topoisomerase I-camptothecin-DNA ternary cleavable complex in a cell-free SV40 DNA replication system. The formation of topoisomerase I-camptothecin-DNA-cleavable complexes on the replication template efficiently and irreversibly inhibited DNA replication. Two aberrant forms of replication products were produced whose abundance varied with the concentrations of exogenously added topoisomerase I and camptothecin. At low concentrations of topoisomerase I and camptothecin, the major aberrant DNA replication product was close-to-unit-length-linear DNA, while at higher concentrations the predominant product was close-to-dimer-size-linear DNA. Analysis of these aberrant replication products has suggested a "collision" model in which the interaction between an advancing replication fork and a topoisomerase I-camptothecin-DNA-cleavable complex results in irreversible arrest of the replication fork and the formation of a double-strand DNA break at the fork. Concomitant with fork arrest and fork breakage, the reversible cleavable complex was converted into a topoisomerase I-linked DNA break. We propose that one or several of these events triggers S-phase-specific cell killing and G₂-phase cell cycle arrest.

¹ This work was supported by NIH Grants CA39962 and CA40884. L. F. L. is the recipient of the George Hitchings Award from Burrough Wellcome Co.

² To whom requests for reprints should be addressed, at Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854.

Received 8/ 5/93. Accepted 10/11/93.

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