Augmentation of nonsense mediated decay by rapamycin
| Autor: | Rocio T. Martinez-Nunez, Hanane Ennajdaoui, Miles Rush, Linnea I. Jansson, Doyle Coyne, Tilman Sanchez-Elsner, Jeremy R. Sanford |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0303 health sciences
Cap binding complex EIF4E Nonsense-mediated decay Context (language use) Translation (biology) Biology Ribosome Molecular biology Cell biology Messenger RNP 03 medical and health sciences 0302 clinical medicine Polysome 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/028332 |
| Popis: | RNA surveillance by the Nonsense Mediated Decay (NMD) pathway eliminates potentially deleterious transcripts containing Premature Termination Codons (PTCs). The transition from a pioneering round of translation to steady state translation is hypothesized to be a major checkpoint in this process. One hallmark of mRNAs licensed for translation is the exchange of 7-methylguanosine cap binding proteins. However, mRNAs undergoing steady state translation are also NMD substrates, raising mechanistic questions about the NMD checkpoint. To test the role of cap binding proteins in NMD, we modulated the protein composition of cytoplasmic messenger ribonucleoprotein particles (mRNPs) with the naturally occurring macrolide rapamycin. We demonstrate that despite well-documented attenuation of cap-dependent mRNA translation, rapamycin can augment NMD. Rapamycin-treatment significantly reduces the levels of endogenous and exogenous PTC-containing mRNA isoforms in a dose- and UPF1- dependent manner. PTC-containing transcripts exhibit a shorter half-life upon rapamacyin-treatment as compared to non-PTC isoforms. Rapamycin also causes depletion of PTC-containing mRNA isoforms from polyribosomes, suggesting that actively translating ribosomes can transition between low and high NMD states. Importantly, mRNPs show depletion of eIF4E and retention of the nuclear Cap Binding Complex (CBC) in rapamycin-treated cells. Our data demonstrate that rapamycin potentiates pioneer-like mRNP context thereby decreasing NMD evasion. |
| Databáze: | OpenAIRE |
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