Cryptic Transcription Mediates Repression of Subtelomeric Metal Homeostasis Genes

Nonsense-mediated mRNA decay (NMD) prevents the accumulation of transcripts bearing premature termination codons. Here we show that Saccharomyces cerevisiae NMD mutants accumulate 5′–extended RNAs (CD-CUTs) of many subtelomeric genes. Using the subtelomeric ZRT1 and FIT3 genes activated in response to zinc and iron deficiency, respectively, we show that transcription of these CD-CUTs mediates repression at the bona fide promoters, by preventing premature binding of RNA polymerase II in conditions of metal repletion. Expression of the main ZRT1 CD-CUT is controlled by the histone deacetylase Rpd3p, showing that histone deacetylases can regulate expression of genes through modulation of the level of CD-CUTs. Analysis of binding of the transcriptional activator Zap1p and insertion of transcriptional terminators upstream from the Zap1p binding sites show that CD-CUT transcription or accumulation also interferes with binding of the transcriptional activator Zap1p. Consistent with this model, overexpressing Zap1p or using a constitutively active version of the Aft1p transcriptional activator rescues the induction defect of ZRT1 and FIT3 in NMD mutants. These results show that cryptic upstream sense transcription resulting in unstable transcripts degraded by NMD controls repression of a large number of genes located in subtelomeric regions, and in particular of many metal homeostasis genes

Cytoplasmic mRNA surveillance pathways

International audienceDuring mRNA synthesis and maturation, the introduction of errors can strongly influence the expression of certain genes and/or the activity of the proteins for which they encode. To minimise these defects, eukaryotic cells have evolved several cytoplasmic and translation-dependent quality control pathways aimed at detecting and degrading mRNAs that would lead to the production of aberrant proteins. The nonsense-mediated mRNA decay pathway (NMD) clears cells from mRNAs harbouring premature in-frame stop codons. Two other pathways (NSD for nonstop decay and NGD for No-Go decay) degrade mRNAs on which ribosomes have stalled during elongation. In this chapter, we describe the current knowledge on the biological roles and molecular mechanisms of these surveillance pathways, which were mainly unravelled using baker’s yeast as model system