TFIID functions

Several functions of TFIID in transcription regulation have been proposed. These roles include promoter recognition, coactivator function, and several enzymatic activities (Pugh, 2000). Each of these is discussed in detail below. 

TFIID is the only GTF with intrinsic DNA sequence specificity and is responsible for nucleating the assembly of Pol II preinitiation complex at core promoters. The interaction between TFIID and core promoter is mediated by the affinity of several specific subunits for distinct core promoter elements (Verrijzer and Tjian, 1996). Because TBP functions in transcription by all three nuclear RNA polymerases, these specific interactions help TFIID to distinguish different promoter structures and properly direct Pol II transcription machinery to its target genes. 

The first core promoter element identified was an A/T-rich sequence located upstream of the transcription start site by 25—30 bp in higher eukaryotes, and at a variable distance between 60 and 120 bp in yeast. This element, with the consensus TATAAA, was named the TATA box. TBP interacts with the minor groove of this element and induces a bend in the promoter DNA (Burley and Roeder, 1996). This bending of DNA may be important for coordinating or stabilizing PIC assembly or may play a role in bringing transcription factors closer to the PIC. 

Sequences surrounding the TATA box may also contribute to specific TFIID-core promoter interaction. A study on TAF1 indicates that it functions as a core promoter selectivity factor (Shen and Green, 1997). Using promoter-mapping strategies, it has been shown that the region of a core 

In conclusion, TFIID interacts with the core promoter elements through many specific pairs of protein—DNA interaction. These interactions allow TFIID to distinguish different promoter structures and respond properly to various regulatory signals. 

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Martinez E., Chiang C.-M., Ge H., Roeder R. G. (1994) TATA-binding protein-associated factor(s) in TFIID function through the initiator to direct basal transcription from a TATA-less class II promoter. EMBO J 13 3115. 

The formation of the PIC described above is based on the sequential addition of purified components in in vitro experiments. An essential feature of this model is that the assembly takes place on the DNA template. Accordingly, transcription activators, which have autonomous DNA binding and activation domains (see Chapter 39), are thought to function by stimulating either PIC formation or PIC function. The TAF coactivators are viewed as bridging factors that communicate between the upstream activators, the proteins associated with pol II, or the many other components of TFIID. This view, which assumes that there is stepwise assembly of the PIC—promoted by various interactions between activators, coactivators, and PIC components— is illustrated in panel A of Figure 37-10. This model was supported by observations that many of these proteins could indeed bind to one another in vitro. 

Nakatani, Y., Horikoshi, M., Brenner, M., Yamamoto, T., Besnard, F., Roeder, R. G., and Freese,E. (1990). Adownstream initiation element required for efficient TATA box binding and in vitro function of TFIID. Nature 348 86-88. 

Transcriptional activators can intervene as regulators at various steps in the initiation of transcription. They can interact with components of TFIID, as well as with components of RNA polymerase II, to stimulate transcription. Regulated transcription generally requires the aid of further protein components, which are commonly termed coactivators (see 1.4.3.2). An understanding of the details of coactivator function is only just emerging. 

Fig. 1.34 Activators and coactivators of transcription intiation. The figure shows the function of three groups of proteins that function as coactivators. The general cofactors mediate the interactions between the specific transcription activators and the TFIID complex as well as with various forms of the RNA polymerase II holoenzyme. The TAFs are components of the TFIID complex and serve as contact points for specific transcription activators. The mediators are components of various forms of holoenzymes of RNA polymerase II. SRB proteins belong to the class of mediators, which, among other things, interacts with the CTD of RNA polymerase. The simphfied diagram does not show the interactions with chromatin.

The TAFs are components of TFIID (see table 1.1) and are required for a regulated transcription (review Verriijzer and Tijan 1996, Bmley and Roeder, 1996 ). Thus, the stimulation of transcription by the transcriptional activators Spl and NTF-1 depends upon the presence of specific TAFs in the TFllD complex. The TAFs mediate interactions between the transcriptional activators and the TFllD complex in many cases direct protein-protein interactions could be demonstrated between the activators and TAFs. Some of the TAFs possess additional enzymatic activities which allow them to participate in the regulation of transcription. By this token, the histone acetylase and protein kinase activity of TAFn250 is ascribed a regulatory function in the remodeling of chromatin and in the control of the activity of the basal transcription factors. 

In one model it is assumed that transcriptional activators and coactivators increase the efficiency of formation of the pre-initiation complex. This function includes a restructuring of chromatin at the transcription start site. In this context the formation of the TFIID complex at the promoter plays an important role. 

Another important coactivator consists of 20 or more polypeptides in a protein complex called mediator (Fig. 28-27) the 20 core polypeptides are highly conserved from fungi to humans. Mediator binds tightly to the carboxyl-terminal domain (CTD) of the largest subunit of Pol II. The mediator complex is required for both basal and regulated transcription at promoters used by Pol II, and it also stimulates the phosphorylation of the CTD by TFIIH. Both mediator and TFIID are required at some promoters. As with TFIID, some DNA-binding transactivators interact with one or more components of the mediator complex. Coactivator complexes function at or near the promoter s TATA box. 

Phil Sharp and Leonard Guarente showed that at least four transcription factors are required in addition to polymerase II for initiation from the major late promoter of adenovirus. In vitro studies indicate that these factors assemble in an orderly fashion (see fig. 28.12b). First the TFIID complex binds to the TATA box. Sequential binding of TFIIA, TFIIB, RNA polymerase II, and TFIIE follow. It is believed that this multifactor complex functions for a large number of eukaryotic promoters that contain TATA boxes. 

J. D. Fondell, M. Guermah, S. Malik, and R G. Roeder. Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFIID. Proc Nad Acad. Sci, VSA, 96 (5), 1959-1964, 1999. 

Y. Nakatani, et al. A downstream initiation element required for efficient TATA box binding and in vitro function of TFIID. Nature 348 (1990) 86-8. 

Pugh, B. E, and Tjian, R. (1992). Diverse transcriptional functions of the multisubunit eukaryotic TFIID complex. J. Biol. Chem. 267, 679-682. 

TFIID and its individual subunits have been subjected to intense study. As will be discussed below, complementary information from biochemical, genetic, and structural studies has shown, and will continue to give, a clearer picture of the forms and functions of this crucial component of the transcription machinery. 

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