Initiation of transcription

Both amantadiae and rknantadiae have been found to reduce the duration of influenza A-iaduced fever and malaise, and to lessen viral shedding. Prophylactic treatment has been recommended for high risk patients (95). It has been suggested that, ia the presence of amantadine, the influenza vims attaches normally to cells, but once iaside the ceU the vims fails to initiate repHcation. Thus amantadine appears to inhibit the initiation of transcription at an early stage between uncoating and viral-specific RNA synthesis (96). 

The promoter proximal elements are usually 100 to 200 base pairs long and relatively close to the site of initiation of transcription. Within each of these elements there are DNA sequences specifically recognized by several different transcription factors which either interact directly with the preinitiation complex or indirectly through other proteins. 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

Other steps of RNA synthesis such as elongation or termination also control the abundance of proteins. These are less well understood than the initiation of transcription described here. 

The intracellular mechanisms that relay glutamate receptor activation to transcription constitute a much-studied field. Small, monomeric GTPases are important activators or silencers of signaling pathways that lead to changes in gene transcription. A final step in these pathways is the activation of transcription factors that cause initiation of transcription. 

The detailed mechanisms involved in CREB phosphorylation were first established for the cAMP pathway. A first messenger that increases cAMP concentrations leads to activation of PKA and to translocation of the free catalytic subunit of the protein kinase into the nucleus, where it phosphorylates CREB on serine 133. Such phosphorylation then promotes the binding of CREB to a CREB-binding protein (CBP). CBP, upon binding CREB, interacts directly with the RNA polymerase II complex, which mediates the initiation of transcription. In most cases, such interactions lead to the activation of transcription, although it is possible that the expression of some genes may be repressed. 

Figure 1. Schematics of the effect of mH2A on transcription, (a) The mobiUzation of conventional promoter nucleosome by the chromatin remodeling complex generated a nucleosome-free promoter, which allowed the binding of the transcription factors and transcription to proceed, (b) MacroH2A nucleosome cannot be mobilized by die chromatin remodeling complex and die transcriptions factors are unable to bind macroH2A nucleosome containing promoter, which results in inhibition of the initiation of transcription. (See Colour Plate 8.)...

There is a single prokaryotic RNA polymerase that synthesizes all types of RNA in the cell. The core polymerase responsible for making the RNA molecule has the subunit structure Ojpp. A protein factor called sigma (a) is required for the initiation of transcription at a promoter. Sigma factor is released immediately after initiation of transcription. Termination of transcription sometimes requires a protein called rho (p) faaor. This enzyme is inhibited by rifampin. Actinomycin D binds to the DNA preventing transcription. 

Initiation of transcription Promoter (-10) TATAAT and (-35) sequence Sigma initiation sub-unit required to recognize promoter ib omoter (-25) TATA and (-70) CAAT Transcription fectors (TFIID) bind promoter... 

Specific transcription factors bind to enhancer regions or, in a few cases, to silencers and mod-ciate the formation of the initiation complex, thus regulating the rate of initiation of transcription. Each gene contains a variety of enhancer or silencer sequences in its regulatory region. The exact combination of specific transcription factors available (and active) in a particular cell at a particular time determines which genes will be transcribed at what rates, because specific transcription factors are proteins, their expression can be cell-type specific.. Additionally, hormones may regulate the activity of some specific transcription factors. Examples include steroid receptors and the CREB protein. 

These discontinuities in the TATA region may be an expression of structural features which are an inherent part of the TATA sequence possibly associated with stacking modifications. This might be of biological interest, since the base sequence TATA is one of the common signals which is used in the initiation of transcription by SNA polymerase. 

Cis-acting DNA elements can he near the start site of transcription or be quite distanced from it. Fmthermore, there are examples among eucaryotes in which the cis element is foimd within the transcribed region. If the cis element is located far from the site of action and its effect is also orientation-independent, then it is termed an enhancer. Fmthermore, one frequently observes in eucaryotes so called composite control regions which contain various cis elements. In this case, several transcription factors act cooperatively in the initiation of transcription. Examples for such cooperative effects are observed among the genes controlled by nuclear receptors. 

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. 

---