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2017 ; 45
(6
): 3448-3459
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Modulation of nonsense mediated decay by rapamycin
#MMPMID27899591
Martinez-Nunez RT
; Wallace A
; Coyne D
; Jansson L
; Rush M
; Ennajdaoui H
; Katzman S
; Bailey J
; Deinhardt K
; Sanchez-Elsner T
; Sanford JR
Nucleic Acids Res
2017[Apr]; 45
(6
): 3448-3459
PMID27899591
show ga
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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