The Zap1 transcriptional activator negatively regulates translation of the RTC4 mRNA through the use of alternative 5 transcript leaders

The zinc-responsive transcription activator Zap1 plays a central role in zinc homeostasis in the budding yeast Saccharomyces cerevisiae. In zinc-deficient cells, Zap1 binds to zinc responsive elements in target gene promoters and activates gene expression. In most cases, Zap1-dependent gene activation results in increased levels of mRNAs and proteins. However, Zap1-dependent activation of RTC4 results in increased levels of the RTC4 mRNA and decreased levels of the Rtc4 protein. This atypical regulation results from Zap1-mediated changes in the transcriptional start site for RTC4 and the production of a RTC4 transcript with a longer 5 leader. This long RTC4 transcript contains small upstream open reading frames that prevent translation of the downstream RTC4 ORF. The new studies with Zap1 highlight how a transcriptional activator can facilitate decreased protein expression.