Transcriptional enhancement by acidic activators

Transcriptional regulatory mechanisms are fundamentally similar in eukaryotic organisms [1,2]. Components of the RNA polymerase II (Pol II) machinery are highly conserved and, in some cases, functionally interchangeable. Transcriptional activators with similar DNA-binding specificities are present from yeast to human, and acidic activation domains stimulate transcription across a wide range of species. Promoters typically contain multiple protein binding sites, and efficient activation generally requires the combinatorial and synergistic action of activators that can function far from the initiation site. This review focuses on molecular mechanisms of transcriptional activation that occur under physiological conditions, with particular emphasis on studies carried out in the yeast Saccharomyces cerevisiae. Activator proteins stimulate gene expression via a transcriptional activation domain that is functionally distinct, and usually physically separate, from the DNA-binding domain. Activation domains often contain short acidic regions that function autonomously when fused to heterologous DNA-binding domains. Negative charge is clearly important, but hydrophobic residues and other features that are poorly understood at the structural level also influence the level of transcriptional activation [3,4]. Because acidic activators function across species, the molecular target(s) of acidic activation domains must be functionally conserved. It is generally believed that acidic activation domains contact general transcription factors assembled at the TATA and initiator elements. In vitro, acidic activation domains can interact directly with the TATA-binding protein (TBP)[5,6], TBP-associated factors (TAFs) that are components of the TFIID complex [7,8], TFIIA [9], TFIIB [10], TFIIF [11], TFIIH [12], and the C-terminal tail of Pol II [13]. Acidic activation domains can stimulate formation of a TFIID-TFIIA-TATA element complex [14-16], recruit-