Evidence that the Upf1-related molecular motor scans the 3′-UTR to ensure mRNA integrity

Abstract

Upf1 is a highly conserved RNA helicase essential for nonsense-mediated mRNA decay (NMD), an mRNA quality-control mechanism that degrades aberrant mRNAs harboring premature termination codons (PTCs). For the activation of NMD, UPF1 interacts first with a translation–terminating ribosome and then with a downstream exon–junction complex (EJC), which is deposited at exon–exon junctions during splicing. Although the helicase activity of Upf1 is indispensable for NMD, its roles and substrates have yet to be fully elucidated. Here we show that stable RNA secondary structures between a PTC and a downstream exon–exon junction increase the levels of potential NMD substrates. We also demonstrate that a stable secondary structure within the 3′-untranslated region (UTR) induces the binding of Upf1 to mRNA in a translation-dependent manner and that the Upf1-related molecules are accumulated at the 5′-side of such a structure. Furthermore, we present evidence that the helicase activity of Upf1 is used to bridge the spatial gap between a translation–termination codon and a downstream exon–exon junction for the activation of NMD. Based on these findings, we propose a model that the Upf1-related molecular motor scans the 3′-UTR in the 5′-to-3′ direction for the mRNA-binding factors including EJCs to ensure mRNA integrity.