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) Diploid cell

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Mitotic growth

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Meiosis

Sporulation transcription requires a combination of two factors—neither of which can activate target genes alone.

a2-MCM1 and a2-a1 Complexes Repress Transcription

Highly specific binding occurs as a consequence of the interaction of a2 with other transcription factors at different sites in DNA. Flanking the P box in each a-specific URS are two a2-binding sites. Both MCM1 and a2 can bind independently to an a-specific URS with relatively low affinity. However, in a cells highly cooperative, simultaneous binding of both a2 and MCM1 proteins to these sites occurs with high affinity. This high-affinity binding represses transcription of a-specific genes, ensuring that they are not expressed in a cells and diploid cells (see Figure 22-12b, righi). MCM1 promotes binding of a2 to an a-specific URS by orienting the two DNA-binding domains of the a2 dimer to the a2-binding sequences in this URS. Since a dimeric a2 molecule binds to both sites in an a-specific URS, each DNA site is referred to as a half-site. The relative positions of both half-sites and their orientation are highly conserved among different a-specific URSs.

Combinations of transcription factors create additional specificity in gene regulation. The presence of numerous a2-binding sites in the genome and the "relaxed" specificity of a2 protein may expand the range of genes that it can regulate. For instance, in a/a diploid cells, a2 forms a heterodimer with a1 that represses both haploid-specific genes and the gene encoding a1 (see Figure 22-11c). The example of a2 suggests that relaxed specificity may be a general strategy for increasing the regulatory range of a single transcription factor.

Pheromones Induce Mating of a and a Cells to Generate a Third Cell Type

An important feature of the yeast life cycle is the ability of hap-loid a and a cells to mate, that is, attach and fuse giving rise to a diploid a/a cell (see Figure 1-5). Each haploid cell type secretes a different mating factor, a small polypeptide pheromone, and expresses a cell-surface G protein-coupled receptor that recognizes the pheromone secreted by cells of the other type. Thus a and a cells both secrete and respond to pheromones (Figure 22-13). Binding of the mating factors to their receptors induces expression of a set of genes encoding proteins that direct arrest of the cell cycle in G1 and promote attachment/fusion of haploid cells to form diploid cells. In the presence of sufficient nutrients, the diploid cells will continue to grow. Starvation, however, induces diploid cells to progress through meiosis, each yielding four haploid spores. If the environmental conditions become conducive to vegetative growth, the spores will germinate and undergo mitotic division.

Studies with yeast mutants have provided insights into how the a and a pheromones induce mating. For instance, haploid yeast cells carrying mutations in the sterile 12 (STE12) locus cannot respond to pheromones and do not

â–˛ FIGURE 22-13 Pheromone-induced mating of haploid yeast cells. The a cells produce a mating factor and a receptor; the a cells produce a factor and a receptor. Binding of the mating factors to their cognate receptors on cells of the opposite type leads to gene activation, resulting in mating and production of diploid cells. In the presence of sufficient nutrients, these cells will grow as diploids. Without sufficient nutrients, cells will undergo meiosis and form four haploid spores.

mate. The STE12 gene encodes a transcription factor that binds to a DNA sequence referred to as the pheromone-responsive element, which is present in many different a- and a-specific URSs. Binding of mating factors to cell-surface receptors induces a cascade of signaling events, resulting in phosphorylation of various proteins including the Ste12 protein (see Figure 14-24). This rapid phosphorylation is correlated with an increase in the ability of Ste12 to stimulate transcription. It is not yet known, however, whether Ste12 must be phosphorylated to stimulate transcription in response to pheromone.

Interaction of Ste12 protein with DNA has been studied most extensively at the URS controlling transcription of STE2, an a-specific gene encoding the receptor for the a pheromone. Pheromone-induced production of the a receptor encoded by STE2 increases the efficiency of the mating process. Adjacent to the a-specific URS in the STE2 gene is a pheromone-responsive element that binds Ste12. When a cells are treated with a pheromone, transcription of the STE2 gene increases in a process that requires Ste12 protein. Ste12 protein has been found to bind most efficiently to the pheromone-responsive element in the STE2 URS when MCM1 is simultaneously bound to the adjacent P site. We saw previously that MCM1 can act as an activator or a repressor at different URSs depending on whether it complexes with a1 or a2. In this case, the function of MCM1 as an activator is stimulated by the binding of yet another transcription factor, Ste12, whose activity is modified by extracellular signals.

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