Negative Regulation of Transcription Occurs in Eukaryotes

Simple repressors are common in prokaryotes, but rarely found in eukaryotes. Those examples of repressors that do exist are usually found in simpler, single-celled eukary-otes, such as yeast. Although repressors are rare in eukaryotes, this does not mean that negative regulation itself is uncommon. On the contrary, some form of negative control is vital to most of the complex regulatory circuits found in higher organisms. Generally, negative signals act by hindering activator proteins in some manner.

One obvious way to obstruct an activator is to occupy its recognition site on the DNA and so prevent the activator from binding. An example of this concerns the CAAT box, often found in eukaryotic promoters. Activation of the sea urchin H2B gene occurs in the testis only and requires, among other things, the binding of the activator protein CTF to the CAAT sequence. However, the CAAT-displacement protein (CDP) may also occupy the CAAT box and prevent binding of the activator. This occurs in embryonic tissue and prevents premature expression of testis-specific genes. The presence of CDP prevents assembly of the transcriptional apparatus. Note, however, that CDP does not block the binding site for RNA polymerase as a classical bacterial repressor would do (Fig. 10.07).

Another example of negative regulation involves the MyoD transcription factor, which induces a set of genes specifically needed for formation of muscle cells. MyoD is produced only in cells destined to differentiate into muscle tissue. It is a member of the large class of basic helix-loop-helix (bHLH) proteins. As discussed in Ch. 7, the helix-loop-helix is a widespread motif found in DNA-binding proteins. The basic HLH proteins share a stretch of basic amino acids, located next to the first helix, which helps in binding DNA.

HLH proteins bind to DNA as dimers. If both partners have a basic region, the dimer can bind to DNA. Basic HLH proteins usually function as heterodimers consisting of a tissue-specific bHLH protein plus one of the widely expressed bHLH proteins known as E-proteins. By itself, MyoD dimerizes poorly. In order to bind DNA, MyoD must form mixed dimers with E12 or E47. These are also basic HLH proteins that are alternative splicing products from the same gene, E2A. They are similar in shape and structure to MyoD, but unlike MyoD, they are expressed in all tissues. The

CAAT box A sequence often found in the upstream region of eukaryotic promoters and which binds transcription factors heterodimer Dimer composed of two different subunits

MyoD A eukaryotic transcription factor that takes part in muscle cell differentiation negative control See negative regulation negative regulation Control by a repressor that prevents expression of a gene unless it is somehow removed

FIGURE 10.08 MyoD and Its Alternative Partners

A) MyoD and E12 both possess basic DNA binding domains. When MyoD dimerizes with E12 the dimer therefore binds to DNA. B) In contrast, Id protein lacks a basic region. When MyoD dimerizes with Id, this dimer cannot bind DNA.

MyoD/E12 or MyoD/E47 heterodimer binds to the DNA sequence CAAATG and activates muscle-specific genes.

Other HLH proteins lack the basic region and cannot bind DNA. An example is the Id protein. This binds to MyoD and E12 or E47. The heterodimers formed by Id cannot bind DNA (Fig. 10.08).Thus, the presence of Id protein inhibits differentiation. Id therefore plays a negative role, but without binding to DNA like a true repressor. Id protein is present in large amounts in precursor myoblasts, where it plays a role in restraining MyoD activity. During myoblast differentiation, the level of Id falls and this allows the activation of MyoD.

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