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Effects of nucleosomes and anti-tumor drugs on the catalytic activity of type II DNA topoisomerase from rat testis

Galande, S and Muniyappa, K (1997) Effects of nucleosomes and anti-tumor drugs on the catalytic activity of type II DNA topoisomerase from rat testis. In: Biochemical Pharmacology, 53 (9). pp. 1229-1238.

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To gain insight into the relative catalytic efficiencies of mammalian type I and type II DNA topoisomerases, in the cellular context, we have used naked DNA and DNA incorporated into nucleosomes as substrates. We observed that the relaxation activity of both the enzymes declined with DNA containing increasing densities of nucleosomes; however, kinetic analysis revealed that topoisomerase I seemed less affected than topoisomerase II. The addition of histone H1, in stoichiometric amounts, to naked DNA or minichromosomes lessened the activity of topoisomerase II, and required 7-fold less for complete inhibition when the latter was used as the substrate. To ascertain if the observed differences are specific to topoisomerase II from testis, we examined the effect of nucleosomes on the catalytic efficiency of its isoform from liver. Interestingly, the suppression of relaxation activity of Liver topoisomerase II required substrates containing higher mass ratios of histone octamer/DNA. Studies on the effect of nucleosomes an the action of teniposide displayed significant differences in the kinetics of the reaction, in its IC50 values, and have provided biochemical evidence for the first time that nucleosomes increased inhibition caused by teniposide. Further, this feature appears to be specific for topoisomerase II-directed drugs and is not shared by the generic class of either DNA-intercalating or non-DNA-intercalating ligands.

Item Type: Journal Article
Publication: Biochemical Pharmacology
Publisher: Elsevier Science
Additional Information: Copyright of this article belongs to Elsevier Science.
Keywords: Topoisomerases;nucleosomes;histone H1;unwinding;anti-tumor drugs.
Department/Centre: Division of Biological Sciences > Biochemistry
Date Deposited: 02 Jun 2009 10:52
Last Modified: 19 Sep 2010 05:25
URI: http://eprints.iisc.ac.in/id/eprint/18919

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