Inhibitors of transcription such as 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole and isoquinoline sulfonamide derivatives (H-8 and H-7) promote dephosphorylation of the carboxyl-terminal domain of RNA polymerase II largest subunit.

The RNA polymerase IIO and IIA differ by the extent of phosphorylation in the carboxyl-terminal domain (CTD) of the largest subunit. It has been proposed that the IIA form of RNA polymerase II interacts with the promoter to form a stable preinitiation complex whereas the IIO form would be generated upon entry into initiation of transcription. Phosphorylation of the CTD might be required to release the interaction between the polymerase and the promoter binding factors. In this paper, we show that in the presence of actinomycin D, the phosphorylated IIO form accumulates. In contrast, the dephosphorylated IIA form accumulates while the amount of phosphorylated IIo form decreases in cells treated with CTD-kinase inhibitors such as the nucleoside analog, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole or the isoquinoline sulfonamide derivatives H-7* or H-8. These changes are fast and suggest a very rapid phosphate turnover on the CTD. Transcription is inhibited in intact cells by drug concentrations that are effective in altering CTD phosphorylation, although no causal relationship is established yet. These effects do not concern other cellular functions such as protein synthesis. Thus isoquinoline sulfonamide derivatives might be helpful to further dissect the role of CTD phosphorylation in transcription.