Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

Stable Identifier
R-HSA-975957
Type
Pathway
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

During normal translation termination eRF3 associates with the ribosome and then interacts with PABP bound to the polyadenylate tail of the mRNA to release the ribosome and allow a new round of translation to commence. Nonsense-mediated decay (NMD) is triggered if eRF3 at the ribosome interacts with UPF1, which may compete with PABP (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Rebbapragada and Lykke-Andersen 2009, Bhuvanagiri et al. 2010, Nicholson et al. 2010, Durand and Lykke-Andersen 2011). An exon junction located 50-55 nt downstream of a termination codon is observed to enhance NMD.
Exon-junction complexes (EJCs) are deposited on the mRNA during splicing in the nucleus, remain on mRNAs after transport to the cytosol, and are dislodged by the ribosome as it progresses along the mRNA during the pioneer round of translation (Gehring et al. 2009). EJCs contain the core factors eIF4A-III, Magoh-Y14, and CASC3 as well as the peripheral factors RNPS1, UPF2, and UPF3. UPF2 and UPF3 recruit UPF1 to eRF3 at the terminating ribosome. Thus an EJC downstream of a termination codon will not have been dislodged during translation and will recruit UPF1, triggering NMD.
UPF1 is believed to form a complex containing SMG1, SMG8, and SMG9. In the key regulatory step of NMD SMG1 phosphorylates UPF1. The phosphorylated UPF1 then recruits either SMG6 or SMG5 and SMG7. SMG6 is itself an endoribonuclease that cleaves the mRNA. SMG5 and SMG7 do not have endoribonuclease activty, but are thought to recruit ribonucleases. Nonsense-mediated decay has been observed to involve deadenlyation, decapping, and both 5' to 3' and 3' to 5' exonuclease activities, but the exact degradative pathways taken by a given mRNA are not yet known.
UPF1 also plays roles in Staufen-mediated decay, histone mRNA decay, telomere maintenance, genome integrity, and may play a role in normal termination of translation.

Literature References
PubMed ID Title Journal Year
17531985 mRNA quality control: an ancient machinery recognizes and degrades mRNAs with nonsense codons

Behm-Ansmant, I, Kashima, I, Rehwinkel, J, Saulière, J, Wittkopp, N, Izaurralde, E

FEBS Lett 2007
19859661 Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors

Nicholson, P, Yepiskoposyan, H, Metze, S, Zamudio Orozco, R, Kleinschmidt, N, Muhlemann, O

Cell Mol Life Sci 2010
21496649 SnapShot: Nonsense-Mediated mRNA Decay

Durand, S, Lykke-Andersen, J

Cell 2011
19410547 Disassembly of exon junction complexes by PYM

Gehring, NH, Lamprinaki, S, Kulozik, AE, Hentze, MW

Cell 2009
20795950 NMD: RNA biology meets human genetic medicine

Bhuvanagiri, M, Schlitter, AM, Hentze, MW, Kulozik, AE

Biochem J 2010
17352659 The nonsense-mediated decay RNA surveillance pathway

Chang, YF, Imam, JS, Wilkinson, MF

Annu Rev Biochem 2007
19359157 Execution of nonsense-mediated mRNA decay: what defines a substrate?

Rebbapragada, I, Lykke-Andersen, J

Curr Opin Cell Biol 2009
17671086 Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function

Isken, O, Maquat, LE

Genes Dev 2007
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