Topoisomerase II inhibition prevents anaphase chromatid segregation in mammalian cells independently of the generation of DNA strand breaks.
Yeast temperature-sensitive mutants of DNA topoisomerase II are incapable of chromosome condensation and anaphase chromatid segregation. In mammalian cells, topoisomerase II inhibitors such as etoposide (VP-16-123) have similar effects. Unfortunately, conclusions drawn from work with mammalian cells have been limited by the fact that the standard inhibitors of topoisomerase II also generate DNA strand breaks, which when produced by other agents (e.g. ionizing radiation) are known to affect progression into and through mitosis. Here we show that the anti-tumour agent ICRF-193, recently identified as a topoisomerase II inhibitor operating by a non-standard mechanism, generates neither covalent complexes between topoisomerase II and DNA, nor adjacent DNA strand breaks, in mitotic HeLa. However, the drug does prevent anaphase segregation in HeLa and PtK2 cells, with effects similar to those of etoposide. We therefore conclude that topoisomerase II function is required for anaphase chromosome segregation in mammalian cells, as it is in yeast.
Clarke
D J
DJ
Department of Zoology, University of Cambridge, UK.
Johnson
R T
RT
Downes
C S
CS
D000705:Anaphase / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000502:physiology; D054659:Diketopiperazines; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D007614:Macropodidae; D010879:Piperazines / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
D054659:Diketopiperazines; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D004533:Egtazic Acid; D005047:Etoposide; D004250:DNA Topoisomerases, Type II