title: ICRF-193, an anticancer topoisomerase II inhibitor, induces arched telophase spindles that snap, leading to a ploidy increase in fission yeast.
abstract: ICRF-193 [meso-4,4-(2,3-butanediyl)-bis(2,6-piperazinedione)] is a complex-stabilizing inhibitor of DNA topoisomerase II (topo II) that is used as an effective anticancer drug. ICRF-193 inhibits topo II catalytic activity in vitro and blocks nuclear division in vivo. Here, we examined the effects of ICRF-193 treatment on chromatin behavior and spindle dynamics using detailed live mitotic cell analysis in the fission yeast, Schizosaccharomyces pombe. Time-lapse movie analysis showed that ICRF-193 treatment leads to an elongation of presumed chromatin fibers connected to kinetochores during mid-mitosis. Anaphase spindles begin to arch, and eventually spindle poles come together abruptly, as if the spindle snapped at the point of spindle microtubule overlap in telophase. Segregating chromosomes appeared as elastic clumps and subsequently pulled back and merged. The snapped spindle phenotype was abolished by microtubule destabilization after thiabendazole treatment, accompanied by unequal chromosome segregation or severe defects in spindle extension. Thus, we conclude that ICRF-193-treated, unseparated sister chromatids pulling toward opposite spindle poles produce the arched and snapped telophase spindle. ICRF-193 treatment increased DNA content, suggesting that the failure of sister chromatids to separate properly in anaphase, causes the spindle to break in telophase, resulting in polyploidization.
authors.affiliation: G0 Cell Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa, 904-0495, Japan. nakazawa@oist.jp.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Nakazawa
authors.affiliation: G0 Cell Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa, 904-0495, Japan.|Department of Biological Sciences, BITS, Pilani, Rajasthan, 333031, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mehrotra
authors.affiliation: G0 Cell Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa, 904-0495, Japan.
authors.forename: Orie
authors.initials: O
authors.lastname: Arakawa
authors.affiliation: G0 Cell Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, Okinawa, 904-0495, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yanagida
mesh_terms: D000705:Anaphase / Q000187:drug effects / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics; D048750:Cell Nucleus Division; D002842:Chromatids / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020090:Chromosome Segregation; D054659:Diketopiperazines; D018386:Kinetochores / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis; D010879:Piperazines / Q000494:pharmacology*; D011003:Ploidies; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects* / Q000502:physiology; D013692:Telophase / Q000187:drug effects* / Q000502:physiology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D054659:Diketopiperazines; D010879:Piperazines; D029702:Schizosaccharomyces pombe Proteins; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione