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TF IIF TF IIB

2. Other TATA binding factors I and Pol II form pre-initiation * complex.

Mm mRNA

Mm mRNA

Fig. 13.5 The multistep process of transcription initiation at a eukaryotic promoter. With most promoters, the process begins as shown at the top with assembly of the initiation complex at the TATA box. Upon its full assembly, the DNA template is denatured, and RNA synthesis antiparallel to the template (antisense strand) is initiated. The relative sizes of the proteins involved show how location of the pre-initiation complex at the TATA box is spaced to allow RNA polymerase to begin RNA synthesis about 25—30 bases downstream of it. TF = transcription factor; Pol II = RNA polymerase II.

the cap site as shown in the figure. Formation of the pre-initiation complex around the TATA box can be modulated and facilitated by association of one of a number of transcription factors that bind to specific sequences usually upstream of — but within close proximity to — the cap.

These upstream transcription elements can interact with and stabilize the pre-initiation complex because dsDNA is flexible and can "bend" to allow transcription factors to come near to the TATA-binding protein complex; this bending is diagrammed in Fig. 13.6. The whole promoter region (containing the cap site, TATA box, and proximal transcription factor—binding sites) generally occupies the 60—120 base pairs immediately upstream (5') of the transcription start site.

Other control regions or enhancers can occur significant distances away from the promoter region. Such enhancers also interact with specific proteins and ultimately act to allow transcrip-

Fig. 13.6 The flexibility of DNA allows transcription factors binding at sites upstream of the TATA box to stabilize formation of the pre-initiation complex. Enhancer elements even further upstream (or in some cases, downstream) can also bind activating proteins that can further facilitate and modulate the process.

Activator Activator Activator Activator \

Accessory protein

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Far upstream" sites can activate transcription

Activator Activator Activator Activator \

Accessory protein

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Far upstream" sites can activate transcription

Fig. 13.6 The flexibility of DNA allows transcription factors binding at sites upstream of the TATA box to stabilize formation of the pre-initiation complex. Enhancer elements even further upstream (or in some cases, downstream) can also bind activating proteins that can further facilitate and modulate the process.

Activation

/www tion factors to associate with the DNA relatively near the promoter; the process is also shown in Fig. 13.6. Enhancers appear to help displace histones from the transcription template and therefore facilitate the rate of transcription initiation from a given promoter. Unlike the core promoter element itself, however, enhancers serve only to regulate and augment transcription, and the promoter that they act on can mediate measurable transcription in their absence. Enhancers themselves may be subject to modulation of activity by factors stimulating the cell to metabolic activity, such as cytokines and steroid hormones.

Control of initiation of eukaryotic transcription

Like with prokaryotes, controlling the access of RNA polymerase and associated enzymes with the gene to be transcribed to a large measure controls eukaryotic transcription. The process is complicated by the nature of the transcription template (chromatin), the number of regulatory proteins whose access must be controlled, and the need to transmit signals from the cell exterior through the cytoplasm to the nucleus where transcription occurs. The broadest level of control of transcription, one that mediates transcriptional regulation during development, is at the level of chromatin structure. Expression of large portions of cellular chromosomes can be essentially permanently repressed by methylation of DNA followed by its association with specific DNA-binding proteins and nonacetylated histones into condensed hetero chromatin (Fig. 13.7a). Although such regions of the chromosome can be derepressed under certain conditions, such as the abnormal release from replication control associated with tumor growth, normally this is an irreversible process.

Dispersed, euchromatin contains those genes that are normally transcribed in the cell. As described in the preceding section, the binding of transcription factors, RNA polymerase, and the acetylation of the associated histones allowing for an open, accessible, structure is regulated by the presence of regulatory proteins binding to those regulatory DNA sequences controlling the expression of the gene in question.

Many regulatory proteins are sequestered in the cytoplasm in an inactive form until an extracellular signal interacts with its cellular receptor leading to a signal transduction cascade involving covalent modification of target proteins followed by their migration to the nucleus and activation of the target genes. While there are a huge number of extracellular signals, a given cell can only recognize those for which it has specific receptors. These receptors and the cascades that they induce can be divided into a relatively small number of pathways leading to the reversible modification of target proteins (often by phosphorylation). The activation of the a interferon response described in Chapter 8, Part II is shown in Fig. 13.7(b). As shown, the

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