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Inhibition of DNA topoisomerase II by ICRF-193 induces polyploidization by uncoupling chromosome dynamics from other cell cycle events.
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MedLine Citation:
PMID:  8089169     Owner:  NLM     Status:  MEDLINE    
ICRF-193, a novel noncleavable, complex-stabilizing type topoisomerase (topo) II inhibitor, has been shown to target topo II in mammalian cells (Ishida, R., T. Miki, T. Narita, R. Yui, S. Sato, K. R. Utsumi, K. Tanabe, and T. Andoh. 1991. Cancer Res. 51:4909-4916). With the aim of elucidating the roles of topo II in mammalian cells, we examined the effects of ICRF-193 on the transition through the S phase, when the genome is replicated, and through the M phase, when the replicated genome is condensed and segregated. Replication of the genome did not appear to be affected by the drug because the scheduled synthesis of DNA and activation of cdc2 kinase followed by increase in mitotic index occurred normally, while VP-16, a cleavable, complex-stabilizing type topo II inhibitor, inhibited all these processes. In the M phase, however, late stages of chromosome condensation and segregation were clearly blocked by ICRF-193. Inhibition at the stage of compaction of 300-nm diameter chromatin fibers to 600-nm diameter chromatids was demonstrated using the drug during premature chromosome condensation (PCC) induced in tsBN2 baby hamster kidney cells in early S and G2 phases. In spite of interference with M phase chromosome dynamics, other mitotic events such as activation of cdc2 kinase, spindle apparatus reorganization and disassembly and reassembly of nuclear envelopes occurred, and the cells traversed an unusual M phase termed "absence of chromosome segregation" (ACS)-M phase. Cells then continued through further cell cycle rounds, becoming polyploid and losing viability. This effect of ICRF-193 on the cell cycle was shown to parallel that of inactivation of topo II on the cell cycle of the ts top2 mutant yeast. The results strongly suggest that the essential roles of topo II are confined to the M phase, when the enzyme decatenates intertwined replicated chromosomes. In other phases of the cycle, including the S phase, topo II may thus play a complementary role with topo I in controlling the torsional strain accumulated in various genetic processes.
R Ishida; M Sato; T Narita; K R Utsumi; T Nishimoto; T Morita; H Nagata; T Andoh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of cell biology     Volume:  126     ISSN:  0021-9525     ISO Abbreviation:  J. Cell Biol.     Publication Date:  1994 Sep 
Date Detail:
Created Date:  1994-10-14     Completed Date:  1994-10-14     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0375356     Medline TA:  J Cell Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1341-51     Citation Subset:  IM    
Laboratory of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Japan.
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MeSH Terms
CHO Cells
Cell Cycle / drug effects*,  genetics*
Cell Line
Cell Survival / drug effects
Chromosomes / drug effects,  physiology*
DNA Topoisomerases, Type II / antagonists & inhibitors,  physiology*
Hela Cells
Nuclear Envelope / drug effects
Piperazines / pharmacology*
Reg. No./Substance:
0/Piperazines; 21416-68-2/ICRF 193; EC Topoisomerases, Type II

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): J Cell Biol
Journal ID (publisher-id): J. Cell Biol.
ISSN: 0021-9525
ISSN: 1540-8140
Publisher: The Rockefeller University Press
Article Information
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Print publication date: Day: 2 Month: 9 Year: 1994
Volume: 126 Issue: 6
First Page: 1341 Last Page: 1351
ID: 2290951
Publisher Id: 94375513
PubMed Id: 8089169

Inhibition of DNA topoisomerase II by ICRF-193 induces polyploidization by uncoupling chromosome dynamics from other cell cycle events

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