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Published online
doi:10.1083/jcb.200611086
The Journal of Cell Biology, Vol. 178, No. 7, 1145-1160
The Rockefeller University Press, 0021-9525 $30.00
© Durand et al.
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Article

Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies



Sébastien Durand1, Nicolas Cougot1, Florence Mahuteau-Betzer2, Chi-Hung Nguyen2, David S. Grierson2, Edouard Bertrand1, Jamal Tazi1, and Fabrice Lejeune1

1 Centre National de la Recherche Scientifique, Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, Montpellier F-34293, France
2 Centre National de la Recherche Scientifique, Laboratoire de Pharmacochimie, Institut Curie, Université Paris-Sud, Orsay F-91405, France

Correspondence to F. Lejeune: fabrice.lejeune{at}igmm.cnrs.fr

In mammals, nonsense-mediated mRNA decay (NMD) is a quality-control mechanism that degrades mRNA harboring a premature termination codon to prevent the synthesis of truncated proteins. To gain insight into the NMD mechanism, we identified NMD inhibitor 1 (NMDI 1) as a small molecule inhibitor of the NMD pathway. We characterized the mode of action of this compound and demonstrated that it acts upstream of hUPF1. NMDI 1 induced the loss of interactions between hSMG5 and hUPF1 and the stabilization of hyperphosphorylated isoforms of hUPF1. Incubation of cells with NMDI 1 allowed us to demonstrate that NMD factors and mRNAs subject to NMD transit through processing bodies (P-bodies), as is the case in yeast. The results suggest a model in which mRNA and NMD factors are sequentially recruited to P-bodies.

Abbreviations used in this paper: CHX, cycloheximide; DCP, decapping protein; EJC, exon junction complex; Fluc, firefly luciferase; Gl, ß globin; GPx1, glutathione peroxidase 1; IP, immunoprecipitation; miRNA, microRNA; MUP, major urinary protein; NMD, nonsense-mediated mRNA decay; NMDI 1, NMD inhibitor 1; P-bodies, processing bodies; PTC, premature termination codon; Rluc, Renilla luciferase; RPA, RNase protection assay; SSC, sodium saline citrate.


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