Initiation of genetic transcription, and its termination

Peter Portin

In the latest issue of Genes & Development William P. Tansey gives a fresh perspective to transcriptional activation (Genes & Development 15: 1045-1050, [2001]). He refers to an article by Chi et al. in the same issue (Genes & Development 15: 1078-1092, [2001]) where they show that phosphorylation of the transcription factor GCN4 by a kinase called Srb10 signals GCN4 destruction by ubiquitin(Ub)-mediated proteolysis. Although the finding that a kinase can regulate protein destruction is not extraordinary - most Ub-mediated proteolysis is regulated by phosphorylation (Hochstrasser, 1996 - Annu. Rev. Genet. 30: 405-439) - what is extraordinary about this story is the fact that Srb10 is also a component of the RNA polymerase II holoenzyme (Liao et al., 1995 - Nature 374: 193-196), suggesting that GCN4 is marked for destruction as a consequence of its ability to activate transcription.

Transcriptional regulation is all about getting RNA polymerase to the right place on the gene at the right time and making sure that it is competent to conduct transcription. Traditional views of this process place most of their emphasis on the events that precede initiation of transcription. We usually imagine a promoter-bound transcriptional activator (or a collection of activators) recruiting components of the basal transcriptional machinery to the DNA, eventually leading to the recruitment of RNA polymerase II and the onset of gene transcription. Although these events play a crucial role in regulating gene expression, they are only half the story. Correct regulation of transcription requires that polymerase not only initiates when and where it should, but that it stops initiating when no longer appropriate. But how are the signals from transcriptional activators, telling RNA polymerase to fire, terminated, asks Tunsey. Is this process governed by chance, with activators simply falling off the promoter at a certain frequency? Or is there some more direct mechanism, whereby activators are aggressively limited from uncontrolled promoter activation? The article of Chi et al. gives an answer to this very question by suggesting that the latter may be true, and provides a mechanism for how a component of the basal transcription machinery can mark the activators it has encountered, sentencing them to an early death or banishing them from the nucleus. This is accomplished by the mechanism quoted above, i.e. Srb10 targets GCN4 for ubiquitin-mediated proteolysis. The ability of the basal transcriptional apparatus to mark activators provides an efficient way to limit activator function and ensures that continuing transcription initiation at a promoter is coupled to the continuing synthesis and activation of transcriptional activators.