title: Modulation of nonsense mediated decay by rapamycin.
abstract: Rapamycin is a naturally occurring macrolide whose target is at the core of nutrient and stress regulation in a wide range of species. Despite well-established roles as an inhibitor of cap-dependent mRNA translation, relatively little is known about its effects on other modes of RNA processing. Here, we characterize the landscape of rapamycin-induced post-transcriptional gene regulation. Transcriptome analysis of rapamycin-treated cells reveals genome-wide changes in alternative mRNA splicing and pronounced changes in NMD-sensitive isoforms. We demonstrate that despite well-documented attenuation of cap-dependent mRNA translation, rapamycin can augment NMD of certain transcripts. Rapamycin-treatment significantly reduces the levels of both endogenous and exogenous Premature Termination Codon (PTC)-containing mRNA isoforms and its effects are dose-, UPF1- and 4EBP-dependent. The PTC-containing SRSF6 transcript exhibits a shorter half-life upon rapamycin-treatment as compared to the non-PTC isoform. Rapamycin-treatment also causes depletion of PTC-containing mRNA isoforms from polyribosomes, underscoring the functional relationship between translation and NMD. Enhanced NMD activity also correlates with an enrichment of the nuclear Cap Binding Complex (CBC) in rapamycin-treated cells. Our data demonstrate that rapamycin modulates global RNA homeostasis by NMD.
authors.affiliation: University of California Santa Cruz, Department of Molecular, Cellular and Developmental Biology, Santa Cruz, CA 95064, USA.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Rocio T
authors.initials: RT
authors.lastname: Martinez-Nunez
authors.affiliation: University of California Santa Cruz, Department of Molecular, Cellular and Developmental Biology, Santa Cruz, CA 95064, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wallace
authors.affiliation: University of California Santa Cruz, Department of Molecular, Cellular and Developmental Biology, Santa Cruz, CA 95064, USA.
authors.forename: Doyle
authors.initials: D
authors.lastname: Coyne
authors.affiliation: University of California Santa Cruz, Department of Molecular, Cellular and Developmental Biology, Santa Cruz, CA 95064, USA.
authors.forename: Linnea
authors.initials: L
authors.lastname: Jansson
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Rush
authors.affiliation: University of California Santa Cruz, Department of Molecular, Cellular and Developmental Biology, Santa Cruz, CA 95064, USA.
authors.forename: Hanane
authors.initials: H
authors.lastname: Ennajdaoui
authors.affiliation: Center for Biomolecular Science and Engineering, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95060, USA.
authors.forename: Sol
authors.initials: S
authors.lastname: Katzman
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Bailey
authors.affiliation: Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Katrin
authors.initials: K
authors.lastname: Deinhardt
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sanchez-Elsner
authors.affiliation: University of California Santa Cruz, Department of Molecular, Cellular and Developmental Biology, Santa Cruz, CA 95064, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Sanford
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D018389:Codon, Nonsense; D039642:Eukaryotic Initiation Factors / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D059365:Nonsense Mediated mRNA Decay / Q000187:drug effects*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D020365:RNA Helicases; D059368:RNA Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D015534:Trans-Activators / Q000502:physiology
chemical_list: D018389:Codon, Nonsense; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D059368:RNA Isoforms; D012333:RNA, Messenger; C489470:SRSF6 protein, human; D015534:Trans-Activators; D000068103:Serine-Arginine Splicing Factors; D020365:RNA Helicases; C101828:UPF1 protein, human; D020123:Sirolimus