a competition between stimulators and antagonists of upf complex recruitment governs human nonsense-mediated mrna decay刺激器和对手之间的竞争upf值复杂的招聘管理人类nonsense-mediated mrna衰变.pdfVIP

PLoS BIOLOGY A Competition between Stimulators and Antagonists of Upf Complex Recruitment Governs Human Nonsense-Mediated mRNA Decay ¤ * Guramrit Singh , Indrani Rebbapragada, Jens Lykke-Andersen Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Boulder, Colorado, United States of America The nonsense-mediated decay (NMD) pathway subjects mRNAs with premature termination codons (PTCs) to rapid decay. The conserved Upf1–3 complex interacts with the eukaryotic translation release factors, eRF3 and eRF1, and triggers NMD when translation termination takes place at a PTC. Contrasting models postulate central roles in PTC- recognition for the exon junction complex in mammals versus the cytoplasmic poly(A)-binding protein (PABP) in other eukaryotes. Here we present evidence for a unified model for NMD, in which PTC recognition in human cells is mediated by a competition between 39 UTR–associated factors that stimulate or antagonize recruitment of the Upf complex to the terminating ribosome. We identify cytoplasmic PABP as a human NMD antagonizing factor, which inhibits the interaction between eRF3 and Upf1 in vitro and prevents NMD in cells when positioned in proximity to the termination codon. Surprisingly, only when an extended 39 UTR places cytoplasmic PABP distally to the termination codon does a downstream exon junction complex enhance NMD, likely through increasing the affinity of Upf proteins for the 3 9 UTR. Interestingly, while an artificial 39 UTR of .420 nucleotides triggers NMD, a large subset of human mRNAs contain longer 39 UTRs but evade NMD. We speculate that these have evolved to concentrate NMD-inhibiting factors, such