Augmentation of nonsense mediated decay by rapamycin

BioRxiv : the Preprint Server for Biology
Rocio T Martinez-NunezJeremy R Sanford

Abstract

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...Continue Reading

Related Concepts

Polyribosomes
Biochemical Pathway
7-methylguanosine
Set of Polysomal Ribosomes
Macrolide Antibiotics
EIF4E gene
Papillary Thyroid Carcinoma
Protein Biosynthesis
RNA Cap-Binding Proteins
RNA Cap Binding

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