Nature Reviews Molecular Cell Biology 3, 30-40 (2002); doi:10.1038/nrm715

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Box 4 | Continuously variable transcriptional initiation 

The key characteristic of this model is that addition of phosphate groups on the transcription factor are regarded not as a stable modification, but as one that can be dynamically turned over by the continuous and opposing action of kinases and phosphatases. If each cycle of transcriptional initiation is linked to a single event of phosphorylation and dephosphorylation, then transcription is not regarded as stably 'on' over the 30 minutes in which the gene is active, but as dynamically shuttling between the 'on' and 'off' states during this period. The pattern of initiation in the 30-minute period during which the gene is active is represented by the spikes in the schematic. This rate could change continuously over the 30-minute period to precisely reflect how kinase activity driven by signalling cascades in the cytoplasm varies over this period. The rate of transcription would therefore reflect the rate of transcription-factor phosphorylation. This would produce tight quantitative coupling between the balance of kinase and phosphatase activities at the transcription factor and the rate of transcriptional initiation at the gene, which would result in the propagation of quantitatively modulated signal-transduction events into the transcriptional phase. This type of model is energetically more costly in terms of continuous ATP use than the stable switch that is depicted in Box 3, but the biological imperative for quantitative gene regulation, especially for IE genes (see main text), could justify the energy cost. Although protein phosphorylation has been used as the illustration here, any event which is reversible and controlled by signal-transduction cascades, for example protein–protein or protein–DNA interactions at the promoter, could support continuously variable gene switches if a single such event is supported by a single cycle of transcription.

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