Modulation of nonsense mediated decay by rapamycin. Issue 6 (29th November 2016)

• Record Type: Journal Article
• Authors: Martinez-Nunez, Rocio T.; Wallace, Andrew; Coyne, Doyle; Jansson, Linnea; Rush, Miles; Ennajdaoui, Hanane; Katzman, Sol; Bailey, Joanne; Deinhardt, Katrin; Sanchez-Elsner, Tilman; Sanford, Jeremy R.
• Is Part Of: Nucleic acids research. Volume 45:Issue 6(2017)
• Page Start: 3448
• Page End: 3459
• Publication Date: 2016-11-29
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkw1109
• Languages: English
• ISSNs: 0305-1048

Abstract

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.