Specific Repression of Transcription

A further significant mechanism of transcription control is the repression of gene expression (review Cowell, 1994 Johnson, 1995). There are two types of gene repression to be distinguished in eucaryotes. On the one hand the chromatin structure can cause an unspecific repression of gene expression (see 1.4.6). On the other hand, analogous to the specific transcriptional activators, there are specific repressors of transcription. Their effect, in contrast to that of vmspecific repressors, is sequence-dependent and thus suitable for selective repression (Fig. 1.40). DNA sequences that mediate repression of transcription factors are termed silencers. 

Specific repressors can exert their influence directly or indirectly. Indirect repression is, for example, if a repressor protein competes with transcriptional activators for the binding site on the promoter. The extent of repression is then determined by the relative affinity of both proteins to the DNA element and their concentration ratios. The DNA-bound repressor in this case does not act as a transcriptional activator. 

A further possibility for indirect repression results from heterodimerization (see 1.4.4.3). Heterodimers between two transcription factors, in which one of the partners possesses a DNA-binding domain with weak affinity, can inactivate a transcriptional activator in a heterodimer complex. Since a strong binding to the DNA element usually requires both subimits of a DNA-binding protein, transcription activation by this type of heterodimer is not possible. 

Direct repressors interact with the basal components of the transcription apparatus or with transcriptional activators to inhibit their activity. Specific repressors, analogous to transcriptional activators, are constructed modularly, with a DNA-binding domain and a repressor domain. The repressive character of such domains has been proven in domain swapping experiments. The mechanism of specific repression remains speculative. The following mechanisms are, however, conceivable  

An interesting and fimctionally important aspect of transcriptional activators is that one and the same protein can act as both an activator and a repressor. The alternative functionality is determined by the sequence environment, the presence of other transcriptional activators (steroid receptors, see ch. 4), by specific repressors or by low molecular weight effectors. Examples are the receptors for vitamin A acid, which, in the absence of its ligand, represses the genes with cognate DNA elements. TTie repression is exerted in the DNA-bound form. In the presence of its hgand, vitamin A acid, the same receptor acts as a transcriptional activator (see ch. 4). 

Many general repressors function via components of the basal transcription machinery, with the TATA box-binding protein TBP as the major target. Repressors like NC2 are known that bind to the TBP on the promotor and can prevent RNA polymerase II holoenzyme from assembling into the initiation complex. In this way, a general repression of class II genes can be achieved. 

The mechanisms of gene-specific repressors are also diverse. Gene-specific repressors may function by binding to transcription activators or by competing with the activator for overlapping binding sites. The extent of repression is then determined 

In summary the following mechanisms of general and specific repression have emerged (see Fig. 1.32)  

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