Mechanisms of gene regulation in the general control of amino acid biosynthesis in Saccharomyces cerevisiae

Abstract

More than 30 unlinked genes encoding enzymes in amino acid biosynthetic pathways are coordinately regulated in Saccharomyces cerevisiae by a system known as general amino acid control. Transcription of all of these genes increases in response to starvation for any amino acid. Regulation by the general control system depends on a 9-base-pair nucleotide sequence, repeated in the 5'-noncoding deoxyribonucleic acid of each structural gene. This sequence is the binding site for the GCN4 protein, a positive regulator of transcription. GCN4 has separate regions for deoxyribonucleic acid binding and transcriptional activation that are strikingly similar to domains in other known regulatory proteins. GCN4 expression is regulated at the translational level by four AUG codons located in the leader of GCN4 messenger ribonucleic acid. The third and fourth AUG codons exert a nearly absolute block to translation of GCN4 protein-coding sequences in nonstarvation conditions. The first and second AUG codons function in starved cells to overcome translational repression. Trans-acting factors encoded by the GCD genes prevent the positive regulatory action of the first and second AUG codons. These factors are antagonized in starvation conditions by the products of three additional GCN genes, leading to increased synthesis of the GCN4 protein. One particular GCN factor, GCN3, has a direct role in negative regulation of the GCD1 and GCD12 gene products. Thus, general amino acid control is a multifaceted system that draws on several strategies of gene regulation to couple expression of amino acid biosynthetic enzymes to environmental changes.