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Modulation of nonsense mediated decay by rapamycin

Modulation of nonsense mediated decay by rapamycin
Modulation of nonsense mediated decay by rapamycin
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.
0305-1048
1-12
Martinez-Nunez, Rocio
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Wallace, Andrew
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Coyne, Doyle
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Jansson, Linnea
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Rush, Miles
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Ennajdaoui, Hanane
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Katzman, Sol
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Bailey, Joanne Louise
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Deinhardt, Katrin
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Sanchez-Elsner, Tilman
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Sanford, Jeremy R.
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Martinez-Nunez, Rocio
a6069f08-55cf-4477-b895-9c4fdd2ee5ee
Wallace, Andrew
94c565bc-4c46-47ef-b67b-fea558f4a97f
Coyne, Doyle
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Jansson, Linnea
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Rush, Miles
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Ennajdaoui, Hanane
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Katzman, Sol
8cad2147-3f1b-4730-b3c6-4c668c7e3c0e
Bailey, Joanne Louise
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Deinhardt, Katrin
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Sanchez-Elsner, Tilman
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Sanford, Jeremy R.
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Martinez-Nunez, Rocio, Wallace, Andrew, Coyne, Doyle, Jansson, Linnea, Rush, Miles, Ennajdaoui, Hanane, Katzman, Sol, Bailey, Joanne Louise, Deinhardt, Katrin, Sanchez-Elsner, Tilman and Sanford, Jeremy R. (2016) Modulation of nonsense mediated decay by rapamycin. Nucleic Acids Research, 1-12. (doi:10.1093/nar/gkw1109). (PMID:27899591)

Record type: Article

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.

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Accepted/In Press date: 28 October 2016
e-pub ahead of print date: 28 November 2016
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 402046
URI: http://eprints.soton.ac.uk/id/eprint/402046
ISSN: 0305-1048
PURE UUID: 7f95b58c-47af-44d7-beaf-38208f0d2a51
ORCID for Katrin Deinhardt: ORCID iD orcid.org/0000-0002-6473-5298

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Date deposited: 13 Jan 2017 14:32
Last modified: 03 Dec 2019 01:37

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Contributors

Author: Rocio Martinez-Nunez
Author: Andrew Wallace
Author: Doyle Coyne
Author: Linnea Jansson
Author: Miles Rush
Author: Hanane Ennajdaoui
Author: Sol Katzman
Author: Joanne Louise Bailey
Author: Jeremy R. Sanford

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