Inhibition of topoisomerase II by ICRF-193 prevents efficient replication of herpes simplex virus type 1.
Cellular topoisomerase II is specifically inactivated by the drug ICRF-193. This compound turns topoisomerase II into a closed clamp that is unable to cleave DNA. We have investigated the effects of this inhibitor on the replication of herpes simplex virus type 1. We show that ICRF-193 at low multiplicities of infection dramatically inhibits viral DNA synthesis and the production of infectious virus. The inhibition is less efficient at high multiplicities of infection. In addition, inhibition of viral DNA synthesis was observed only when ICRF-193 was present during the first 4 h of the infectious cycle. The transient replication of plasmids containing a herpes simplex virus type 1 origin of DNA replication, oriS, was affected by ICRF-193 in the same way. In contrast, neither cellular DNA synthesis nor replication of plasmids containing a simian virus 40 origin of DNA replication was inhibited. The observed effect on herpes simplex virus DNA replication was not caused by a decreased transcription of replication genes inasmuch as the levels of UL8, UL9, UL29, and UL30 rmRNAs were unaffected by the drug. These results suggest that topoisomerase II plays a vital role during the replication of herpes simplex virus type 1 DNA. We speculate that topoisomerase II is involved in the decatenation of newly synthesized daughter molecules.
Hammarsten
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Department of Medical Biochemistry, University of Göteborg, Sweden.
Yao
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Elias
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D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004265:DNA Helicases / Q000235:genetics; D019915:DNA Primase; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000502:physiology*; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D054659:Diketopiperazines; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005090:Exodeoxyribonucleases; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D018741:Replication Origin; D013539:Simian virus 40 / Q000235:genetics; D059005:Topoisomerase II Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
D004279:DNA, Viral; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; C045462:ICP8 protein, Simplexvirus; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; D014764:Viral Proteins; C064565:UL9 protein, Human herpesvirus 1; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D005047:Etoposide; D019915:DNA Primase; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C062021:helicase-primase, Human herpesvirus 1; C043417:DNA polymerase, Simplexvirus; D004265:DNA Helicases; D004250:DNA Topoisomerases, Type II