Transcriptional Repressors

In bacteria we saw that many repressors work by binding to sites that overlap the promoter and thus block binding of RNA polymerase. But we also saw other ways ihoy can work: they can bind to sites adjacent to promoters and, by interacting with polymerase hound there, inhibit the enzyme from initiating transcription. They can also interfere with the action of activators.

[n eukaryotes we see all these except the first (ironically the most common in bacteria). We also see another form of repression, perhaps the most common in eukaryotes, which works as follows: as with activators, repressors can tecruil nucleosome modifiers, but in this case the enzymes have the opposite effects to those recruited by activators— they compact the chromatin or remove groups recognized by the transcriptional machinery. So, for example, histone deacetylases repress transcription by removing actetyl groups from the tails of histones; as we have already seen, the presence of acetyl groups helps transcription. Other enzymes add methyl groups to histone tails, and this frequently represses transcription. These kinds of modification also form the basis of a type of repression caller! "silencing," which we consider in some detail later in this chapter.

These various examples of repression are shown schematically in Figure 17-19. Here we consider just one specific example, the repressor called Migl wliicli, like Cal4, is involved in controlling the GAL genes of the yeast S. cerevisiae.

FIGURE 17-19 Ways in whfch eukaryotic repressors work. Transcription of eukaryotic. genes can be repressed in various ways. These indude the four mechanisms shown in the figure. Part (a) shows that, by binding to a site on DNA that overlaps the binding site of an activator, a repressor can inhibit binding of the activator to a gene, and thus block activation of that gene. In a variation on this theme, a repressor can be a derivative of the same prolan as the activator, but tack the activating region. In another variation, an activator that binds to DNA as a dimer can be inhibited from doing so by a derivative that retains the region of the protein required for dimenzation, but lacks the DNfrbinding domain Such a derivative forms inactive heterodirners with the activator In part (b), a repressor binds to a site on DNA beside an activator and interacts with that activator, occluding its activating region. In part (c), a repressor binds to a site upstream of a gene and, by interacting with the transcriptional machinery at the promoter in some specific way, inhibits transcription initiation. Part (d) shows repression by recruiting histone modifiers that alter nudeosomes in ways that inhibit transenpuon (for example, deacetyiation, as shown here, but also methylation in some cases, or even remodeling at some promoters).

trcU promoter activator^ repressor binding binding site site mechanism:

competition

---r inhibition

Mediator direct repression

Mediator

RNA polymerase I

RNA polymerase I

indirect repression site

FIGURE 17-20 Repression of the CAL1 gene in yeast In the presence of glucose, Migt binds a site between the UASC and the CAL1 promoter. By recruiting the fupl repressing complex, Migl represses expression of CAI. I Repression is s result of deacetylation of local nucieosomes (Topi recruits a deacetylase), and also probably by directly contacting and inhibiting the transcription machinery, in an experiment not shown, it Tup) is fused to a DMA-binding domain, and a site for that domain is placer) upstream of a gene expression of the gene is repressed site

FIGURE 17-20 Repression of the CAL1 gene in yeast In the presence of glucose, Migt binds a site between the UASC and the CAL1 promoter. By recruiting the fupl repressing complex, Migl represses expression of CAI. I Repression is s result of deacetylation of local nucieosomes (Topi recruits a deacetylase), and also probably by directly contacting and inhibiting the transcription machinery, in an experiment not shown, it Tup) is fused to a DMA-binding domain, and a site for that domain is placer) upstream of a gene expression of the gene is repressed

Figure 17-20 shows the GAL genes as we saw (hern earlier (Figure 17-3), hut with the addition of a site, between the Gal4 binding sites and the promoter; this is where, in the presence of glucose, Migl binds and switches off the GAL genes. Thus, just as in E. coli, the cell only makes the enzymes needed to metabolize galactose if the preferred energy source, glucose, is not present. How does Migl repress the GAL genes?

Migl recruits a "repressing complex" containing the Tupl protein. This complex is recruited by many yeast DNA-binding proteins that repress transcription, including the cx2 protein involved in controlling mating-type specific genes we described above. Tupl also has counterparts in mammalian cells. TWo mechanisms have been proposed to explain the repressing effect of Tupl. First, Tup1 recruits histone deacietylases, which deacetylate nearby nudeosomes. Second, Tupl interacts directly with the transcription machinery at the promoter and inhibits initiation.

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