The transcriptional elongation inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole inhibits transcription factor IIH-associated protein kinase.
Regulation of chain elongation by RNA polymerase II can have an important effect on gene expression (Bentley, D. (1995) Curr. Opin. Genet. Dev. 5, 210-216; Yankulov, K., Blau, J., Purton, T., Roberts, S., and Bentley, D. (1994) Cell 77, 749-759); however the mechanisms that control this step in transcription are not well understood. The adenosine analogue 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) has long been used as an inhibitor of RNA polymerase II elongation, but its target is not known. We show that DRB is a potent inhibitor of Cdk-activating kinase, associated with the general transcription factor TFIIH. Two other inhibitors of this kinase, H-7 and H-8, also inhibited transcriptional elongation. Furthermore, TFIIH kinase bound specifically to the herpes simplex virus VP16 activation domain which stimulates polymerase II elongation in addition to initiation (Yankulov, K., Blau, J., Purton, T., Roberts, S., and Bentley, D. (1994) Cell 77, 749-759). Our results suggest that DRB affects transcription by inhibiting the TFIIH-associated kinase and that this kinase functions in the control of elongation by RNA polymerase II.
Yankulov
K
K
ICRF, London, United Kingdom.
Yamashita
K
K
Roy
R
R
Egly
J M
JM
Bentley
D L
DL
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004265:DNA Helicases / Q000378:metabolism; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D017405:Herpes Simplex Virus Protein Vmw65 / Q000096:biosynthesis; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D012319:RNA Polymerase II / Q000378:metabolism*; D018139:Simplexvirus / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism*; D019473:Transcription Factors, TFII; D014158:Transcription, Genetic / Q000187:drug effects*
D004791:Enzyme Inhibitors; D017405:Herpes Simplex Virus Protein Vmw65; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D004004:Dichlororibofuranosylbenzimidazole; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D012319:RNA Polymerase II; D004265:DNA Helicases