Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies.
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.
Durand
Sébastien
S
Centre National de la Recherche Scientifique, Institut de Génétique Moléculaire de Montpellier, Université de Montpellier, Montpellier F-34293, France.
Cougot
Nicolas
N
Mahuteau-Betzer
Florence
F
Nguyen
Chi-Hung
CH
Grierson
David S
DS
Bertrand
Edouard
E
Tazi
Jamal
J
Lejeune
Fabrice
F
D002352:Carrier Proteins / Q000378:metabolism; D018389:Codon, Nonsense / Q000378:metabolism*; D022083:Cytoplasmic Structures / Q000187:drug effects* / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D005095:Exoribonucleases / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D020365:RNA Helicases; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D013816:Thermodynamics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D002352:Carrier Proteins; D018389:Codon, Nonsense; D007211:Indoles; D008869:Microtubule-Associated Proteins; D050505:Mutant Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C515801:SMG5 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C468286:UPF2 protein, human; C030374:indole; D005095:Exoribonucleases; C470512:XRN1 protein, human; D020365:RNA Helicases; C101828:UPF1 protein, human