A position-specific 3′UTR sequence that accelerates mRNA decay

Abstract

The 3′ untranslated regions (3′UTRs) of mammalian mRNAs direct an extensive range of alternative post-transcriptional outcomes, including regulation of mRNA decay and translation, contributing significantly to overall gene regulation. However, our knowledge of the underlying sequences and mechanisms is incomplete. We identified a novel 3′UTR sequence motif in mammals that targets mRNAs for transcript degradation. The motif is found in hundreds of mRNAs and is enriched in transcripts encoding regulatory proteins, such as transcription and signaling factors. Degradation of mRNAs containing the motif is mediated by the CCR4-NOT deadenylation complex. We identified hnRNPs A1 and A2/B1 as trans factors that directly bind to the motif, indicating a novel role for these proteins in deadenylation. Interestingly, a genome-wide analysis of the impact of this new regulatory pathway showed that the most active motifs are located within the 5′ and 3′-terminal portions of 3′UTRs, whereas elements in the center tend to be inactive. The highly position-specific function of the motif adds a new layer of regulation to gene expression mediated by 3′UTRs.