Corepressors

Figure 8.20 Schematic diagrams of docking the trp repressor to DNA in its inactive (a) and active (b) forms. When L-tryptophan, which is a corepressor, hinds to the repressor, the "heads" change their positions relative to the core to produce the active form of the repressor, which hinds to DNA. The structures of DNA and the trp repressor are outlined.

The polypeptide chain of the lac repressor subunit is arranged in four domains (Figure 8.21) an N-terminal DNA-hinding domain with a helix-turn-helix motif, a hinge helix which binds to the minor groove of DNA, a large core domain which binds the corepressor and has a structure very similar to the periplasmic arablnose-binding protein described in Chapter 4, and finally a C-terminal a helix which is involved in tetramerization. This a helix is absent in the PurR subunit structure otherwise their structures are very similar. 

Muliprotein complexes that do not directly bind DNA, but are recruited by sequence-specific transcription factors and mediate their capacity to activate genes (coactivators) and to repress genes (corepressors). 

Another example is a recently discovered second mode of action by which nuclear receptors modulate transcription. In contrast to DNA-binding-dependent mechanisms, cross talk refers here to gene regulation by protein-protein-interaction of nuclear receptors with other transcription factors, such as AP-1 or NF-kB. Consequently, the nuclear receptor acts as a corepressor or coactivator of transcription. 

Enzyme activity ascribed to corepressors, which is the removal of acetyl groups from lysine residues of histone tails. Thereby the assembly of nucleosomes is maintained, which leads to a dense, transcriptional inactive chromatin structure. 

The transcriptional activity of NRs is also modulated by various posttranslational modifications of the receptors themselves or of their coregulatory proteins. Phosphorylation, as well as several other types of modification, such as acetylation, SUMOylation, ubiquitinylation, and methylation, has been reported to modulate the functions of NRs, potentially constituting an important cellular integration mechanism. In addition to the modifications of the receptors themselves, such modifications have been reported for their coactivators and corepressors. Therefore, these different modes of regulation reveal an unexpected complexity of the dynamics of NR-mediated transcription. 

The multiprotein unit that synthesize RNA by copying the sequence information from the leading strand of the DNA. Its activity is tightly controlled by phosphorylation of the C-termal domain (CTD), access to DNA and interaction by general and sequence specific transcription factors and coactivators and corepressors. 

The understanding of diversity in ligand-mediated ER activity was advanced by the discovery of transcriptional cofactors. These proteins, termed coactivators and corepressors, bind the liganded ER and enhance... 

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. 

The core unit of the chromatin, the nucleosome, consists of histones arranged as an octamer consisting of a (H3/ H4)2-tetramer complexed with two histone H2A/H2B dimers. Accessibility to DNA-binding proteins (for replication, repair, or transcription) is achieved by posttranslational modifications of the amino-termini of the histones, the histone tails phosphorylation, acetylation, methylation, ubiquitination, and sumoyla-tion. Especially acetylation of histone tails has been linked to transcriptional activation, leading to weakened interaction of the core complexes with DNA and subsequently to decondensation of chromatin. In contrast, deacetylation leads to transcriptional repression. As mentioned above, transcriptional coactivators either possess HAT activity or recruit HATs. HDACs in turn act as corepressors. 

The cis-acting elements that decrease or repress the expression of specific genes have also been identified. Because fewet of these elements have been smdied, it is not possible to fotmulate genetalizations about their mechanism of action—though again, as for gene activation, chromatin level covalent modifications of histones and other proteins by (repressor)-recruited multisubunit corepressors have been imphcated. 

Figure 43-11. The hormone response transcription unit. The hormone response transcription unit is an assembly of DNA elements and bound proteins that interact, through protein-protein interactions, with a number of coactivator or corepressor molecules. An essential component is the hormone response element which binds the ligand (A)-bound receptor (R). Also Important are the accessory factor elements (AFEs) with bound transcription factors. More than two dozen of these accessory factors (AFs), which are often members of the nuclear receptor superfamily, have been linked to hormone effects on transcription. The AFs can interact with each other, with the liganded nuclear receptors, or with coregulators. These components communicate with the basal transcription complex through a coregulator complex that can consist of one or more members of the pi 60, corepressor, mediator-related, or CBP/p300 families (see Table 43-6).

A small number of proteins, including NCoR and SMRT, comprise the corepressor family. They function, at least in part, as described in Figure 43-2. Another family includes the TRAPs, DRIPs, and ARC (Table 43-6). These so-called mediator-related proteins range in size from 80 kDa to 240 kDa and are thought to be involved in linking the nuclear receptor-coactivator complex to RNA polymerase II and the other components of the basal transcription apparatus. 

In the Gram-positive bacterium Bacillus subtilis (DNA with low G + C content), three Fur-like proteins have been characterized (Bsat et al., 1998). One, called Fur, regulates mainly iron uptake and siderophore biosynthesis. A second one, called PerR, regulates peroxide stress response genes and acts with manganese as corepressor. A third one, Zur, regulates genes for zinc uptake. The Zur protein found in E. coli shows only 25 % identity to the B. subtilis Zur, while the two Fur proteins have 32 % identical amino acids. 

It has been suggested that the effect of light is due to the production of a corepressor interacting with the reaction center bacteriochlorophyll. For more information see the review by Drews23). 

Well-documented cases exist where the estrogens inhibit the expression of some genes. These are usually transcribed by means of the constitutive activity of powerful promoters. The inhibition is a result of the steric interposition of the receptor dimer in the development region of the gene, which thereby recruits corepressors that interrupt the prior instigator effect in the absence of receptor (McKenna et al. 1999 Mester et al. 1995 Smith et al. 1997 Tora et al. 1989). 

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