Interaction between replication forks and topoisomerase I-DNA cleavable complexes: Studies in a cell-free SV40 DNA replication system

Yeou Ping Tsao, Leroy-Fong Liu, Gill Nyamuswa, Robert Silber, Leroy F. Liu

研究成果: 雜誌貢獻文章同行評審

211 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)5908-5914
頁數7
期刊Cancer Research
53
發行號24
出版狀態已發佈 - 十二月 15 1993
對外發佈

ASJC Scopus subject areas

  • 癌症研究
  • 腫瘤科

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