Novobiocin inhibits initiation of RNA polymerase II-directed transcription of the mouse metallothionein-I gene independent of its effect on DNA topoisomerase II.
The requirement for ATP hydrolysis in the initiation of RNA polymerase II (Pol II)-directed transcription and the relationship between ATP and novobiocin action led us to investigate whether novobiocin could inhibit transcription of the mouse metallothionein-I (MT-I) gene. Novobiocin inhibited the MT-I gene transcription in a fractionated rat hepatoma nuclear extract in a dose-dependent manner by direct interaction with a nuclear factor(s). This interaction prevented formation of stable preinitiation complexes but did not affect elongation of MT-I mRNA. Preincubation of the nuclear extract with ATP prevented the action of novobiocin on MT-I gene transcription. Although novobiocin is known to inhibit DNA topoisomerase II, VM-26, a specific inhibitor of this enzyme had no effect on the transcription. These results indicate that novobiocin blocks the Pol II-directed transcription by inhibiting formation of preinitiation complexes at an ATP-dependent step.
Webb
M L
ML
Department of Pharmacology, Pennsylvania State University, College of Medicine, Hershey 17033.
Maguire
K A
KA
Jacob
S T
ST
D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D004262:DNA Restriction Enzymes; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D005796:Genes / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D009675:Novobiocin / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic / Q000187:drug effects*
D009675:Novobiocin; D008668:Metallothionein; D012319:RNA Polymerase II; D004262:DNA Restriction Enzymes; D004250:DNA Topoisomerases, Type II