Sensitivity of RNA synthesis to actinomycin D inhibition is dependent on the frequency of transcription: a mathematical model.
The synthesis of ribosomal RNA is known to be up to 100-fold more sensitive to inhibition by actinomycin D than is messenger RNA. A model is presented here to explain the dose-response kinetics of this inhibition. The basic concept is that on very actively transcribed genes, such as ribosomal DNA, the first bound actinomycin D will sterically affect those densely packed polymerase molecules between it and the promoter, causing them to stack up into the promoter and interfere with the initiation of RNA synthesis. However, on less active genes, where the polymerases are widely spaced, the drug will inhibit individual polymerasas independently and only at the actinomycin blockade. Counteracting these inhibitory effects will be the tendency of genes bound with actinomycin to accumulate additional polymerases. A mathematical model is described which successfully explains previously reported dose-response kinetics of actinomycin inhibition in both frequently and infrequently transcribed genes. The analysis indicates that actinomycin inhibition is dependent on both polymerase packing and on gene size. The dose-response kinetics can be used to estimate both the size and transcriptional efficiency of individual genes. The model is also able to explain several other independent observations regarding the kinetics of inhibition of RNA synthesis by actinomycin.
Miller
M J
MJ
Division of Cancer Etiology, National Cancer Institute, Bethesda 20892.
D003609:Dactinomycin / Q000494:pharmacology*; D008433:Mathematics; D008954:Models, Biological; D012313:RNA / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012335:RNA, Ribosomal / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*
D012335:RNA, Ribosomal; D003609:Dactinomycin; D012313:RNA