Topoisomerase II-DNA complexes trapped by ICRF-193 perturb chromatin structure.
DNA topoisomerase II (topo II) is involved in unlinking replicating DNA and organizing mitotic chromosomes. Topo II is the target of many antitumour drugs. Topo II inhibition results in extensive catenation of newly replicated DNA and may potentially perturb chromatin assembly. Here, we show that the topo II inhibitor ICRF-193 does not prevent the bulk of nucleosome deposition, but perturbs nucleosome spacing in Xenopus egg extracts. This is due to the trapping of topo II-closed clamps on the DNA rather than increased DNA catenation. Inhibition of replicative DNA decatenation has in itself little or no effect on nucleosome deposition and spacing, suggesting that DNA can easily accommodate the sharp bending constraints imposed by the co-habitation of nucleosomes and catenane nodes. Chromatin perturbation by topo II clamps may explain some dominant cellular effects of ICRF-193. Nucleosome-driven bending of precatenane nodes may facilitate their unlinking by topo II during unperturbed replication.
Germe
Thomas
T
Laboratoire de Génétique Moléculaire, Ecole Normale Supérieure, Paris, France.
Hyrien
Olivier
O
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D022004:Chromosome Structures; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004261:DNA Replication; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry*; D054659:Diketopiperazines; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D013094:Spermatozoa / Q000378:metabolism; D014981:Xenopus
D000970:Antineoplastic Agents; D002843:Chromatin; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D009707:Nucleosomes; D010879:Piperazines; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II