How does the GAL4 transcription factor recognize the appropriate DNA binding sites in vivo?

The GAL4 protein of yeast activates the transcription of several genes involved in galactose metabolism. This event requires that GAL4 bind to upstream activation sites with the consensus sequence 5'-CGGN5(T/A)N5CCG-3'. We review the general requirements that must be met for a protein such as GAL4 to find and remain bound to its target site in vivo. Evidence is presented that the GAL4 DNA-binding domain itself has insufficient intrinsic sequence selectivity to fulfill the task of targeting GAL4 to the appropriate sites in a yeast genome. Possible mechanisms by which this selectivity is enhanced in vivo are discussed.