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Nucleic Acids Research, 1990, Vol. 18, No. 15 4553-4559
© 1990

MOLECULAR BIOLOGY

Nucleosome positioning as a critical determinant for the DNA cleavage sites of mammalian DNA topoisomerase in reconstituted Simian virus 40 chromatin

Giovanni Capranico+, Christine Jaxel§, Michel Roberge{varphi}, Kurt W. Kohn and Yves Pommier*

Laboratory of Molecular Pharmacology, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health Bethesda, MD 20892, USA

*To whom correspondence should be addressed

Received March 21, 1990. Revised July 5, 1990. Accepted July 5, 1990.

We have assessed the ability of nucleosomes to influence the formation of mammalian topoisomerase II-DNA complexes by mapping the sites of cleavage induced by four unrelated topoisomerase II inhibitors in naked versus nucleosome-reconstituted SV40 DNA. DNA fragments were reconstituted with histone octamers from HeLa cells by the histone exchange method. Nucleosome positions were determined by comparing micrococcal nuclease cleavage patterns of nucleosome-reconstituted and naked DNA. Three types of DNA regions were defined: 1) regions with fixed nucleosome positioning; 2) regions lacking regular nucleosome phasing; and 3) a region around the replication origin (from position 5100 to 600) with no detectable nucleosomes. Topoisomerase II cleavage sites were suppressed in nucleosomes and persisted or were enhanced in linker DNA and in the nucleosome free region around the replication origin. Incubation of reconstituted chromatin with topoisomerase II protected nucleosome-free regions from micrococcal nuclease cleavage without changing the overall micrococcal nuclease cleavage pattern. Thus, the present results indicate that topoisomerase II binds preferentially to nucleosome-free DNA and that the presence of nucleosomes at preferred DNA sequences influences drug-induced DNA breaks by topoisomerase II inhibitors.

+Istituto Nazionale per lo Studio e la Cura dei Tumori, via G. Venzian 1, 20133 Milan, Italy

§Laboratoire d'Enzymologie des Acides Nucleiques, Universite Pierre et Marie Curie, 96 Blvd. Raspail, 75006 Paris, France

{varphi}ESREC, chemin des Boveresses 155, CH 1066 Epalinges, Switzerland


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