Nonsense-mediated mRNA decay of metal-binding activator MAC1 is dependent on copper levels and 3'-UTR length in Saccharomyces cerevisiae

Abstract

The nonsense-mediated mRNA decay (NMD) pathway was initially identified as a pathway that degrades mRNAs with premature termination codons but is now also recognized as a post-transcriptional gene regulatory pathway which regulates expression of natural mRNAs. Earlier studies demonstrated that regulation of functionally related mRNAs by NMD can be differential and conditional in Saccharomyces cerevisiae. Here, we elucidate the regulation of MAC1 mRNAs by NMD in response to copper, and the role MAC1 3'-UTR plays in this regulation. MAC1 is a copper-sensing transcription factor that regulates high affinity copper transport and is activated under low copper conditions in S. cerevisiae. We found that MAC1 mRNAs were regulated by NMD under normal growth conditions but escape NMD under low and high copper conditions. Mac1p regulated genes escape NMD in conditions where MAC1 mRNAs are NMD sensitive. We also found that the MAC1 3'-UTR contributes to the degradation of the mRNAs by NMD and that MAC1 mRNAs lacking 3'-UTR were stabilized in response to copper deprivation. Taken together, our results demonstrate a novel mechanism of regulating a metal sensing transcription factor, where MAC1 mRNA levels are regulated by NMD and copper, while the activity of Ma1p is controlled by copper levels.