title: Identification of elements in human long 3' UTRs that inhibit nonsense-mediated decay.
abstract: The nonsense-mediated mRNA decay (NMD) pathway serves an important role in gene expression by targeting aberrant mRNAs that have acquired premature termination codons (PTCs) as well as a subset of normally processed endogenous mRNAs. One determinant for the targeting of mRNAs by NMD is the occurrence of translation termination distal to the poly(A) tail. Yet, a large subset of naturally occurring mRNAs contain long 3' UTRs, many of which, according to global studies, are insensitive to NMD. This raises the possibility that such mRNAs have evolved mechanisms for NMD evasion. Here, we analyzed a set of human long 3' UTR mRNAs and found that many are indeed resistant to NMD. By dissecting the 3' UTR of one such mRNA, TRAM1 mRNA, we identified a cis element located within the first 200 nt that inhibits NMD when positioned in downstream proximity of the translation termination codon and is sufficient for repressing NMD of a heterologous reporter mRNA. Investigation of other NMD-evading long 3' UTR mRNAs revealed a subset that, similar to TRAM1 mRNA, contains NMD-inhibiting cis elements in the first 200 nt. A smaller subset of long 3' UTR mRNAs evades NMD by a different mechanism that appears to be independent of a termination-proximal cis element. Our study suggests that different mechanisms have evolved to ensure NMD evasion of human mRNAs with long 3' UTRs.
authors: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors: Kalodiah G
authors: KG
authors: Toma
authors: Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
authors: Indrani
authors: I
authors: Rebbapragada
authors: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
authors: Sébastien
authors: S
authors: Durand
authors: Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado 80309, USA.
authors: Jens
authors: J
authors: Lykke-Andersen
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001483:Base Sequence; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D011132:Polyribosomes / Q000378:metabolism; D020365:RNA Helicases; D050436:Regulatory Elements, Transcriptional / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C112203:CRIPT protein, human; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C486174:TRAM1 protein, human; D015534:Trans-Activators; D020365:RNA Helicases; C101828:UPF1 protein, human
keywords: NMD inhibition; UPF1; long 3′ UTR; nonsense-mediated decay