Reactome | Nonsense-Mediated Decay (NMD)

Nonsense-Mediated Decay (NMD)

Stable Identifier

R-HSA-927802

Type

Pathway

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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The Nonsense-Mediated Decay (NMD) pathway activates the destruction of mRNAs containing premature termination codons (PTCs) (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Neu-Yilik and Kulozik 2008, Rebbapragada and Lykke-Andersen 2009, Bhuvanagiri et al. 2010, Nicholson et al. 2010, Durand and Lykke-Andersen 2011). In mammalian cells a termination codon can be recognized as premature if it precedes an exon-exon junction by at least 50-55 nucleotides or if it is followed by an abnormal 3' untranslated region (UTR). While length of the UTR may play a part, the qualifications for being "abnormal" have not been fully elucidated. Also, some termination codons preceding exon junctions are not degraded by NMD so the criteria for triggering NMD are not yet fully known (reviewed in Rebbapragada and Lykke-Andersen 2009). While about 30% of disease-associated mutations in humans activate NMD, about 10% of normal human transcripts are also degraded by NMD (reviewed in Stalder and Muhlemann 2008, Neu-Yilik and Kulozik 2008, Bhuvanagiri et al. 2010, Nicholson et al. 2010). Thus NMD is a normal physiological process controlling mRNA stability in unmutated cells.
Exon junction complexes (EJCs) are deposited on an mRNA during splicing in the nucleus and are displaced by ribosomes during the first round of translation. When a ribosome terminates translation the A site encounters the termination codon and the eRF1 factor enters the empty A site and recruits eRF3. Normally, eRF1 cleaves the translated polypeptide from the tRNA in the P site and eRF3 interacts with Polyadenylate-binding protein (PABP) bound to the polyadenylated tail of the mRNA.
During activation of NMD eRF3 interacts with UPF1 which is contained in a complex with SMG1, SMG8, and SMG9. NMD can arbitrarily be divided into EJC-enhanced and EJC-independent pathways. In EJC-enhanced NMD, an exon junction is located downstream of the PTC and the EJC remains on the mRNA after termination of the pioneer round of translation. The core EJC is associated with UPF2 and UPF3, which interact with UPF1 and stimulate NMD. Once bound near the PTC, UPF1 is phosphorylated by SMG1. The phosphorylation is the rate-limiting step in NMD and causes UPF1 to recruit either SMG6, which is an endoribonuclease, or SMG5 and SMG7, which recruit ribonucleases. SMG6 and SMG5:SMG7 recruit phosphatase PP2A to dephosphorylate UPF1 and allow further rounds of degradation. How EJC-independent NMD is activated remains enigmatic but may involve competition between PABP and UPF1 for eRF3.

Literature References

PubMed ID	Title	Journal	Year
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
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
21496649	SnapShot: Nonsense-Mediated mRNA Decay Durand, S, Lykke-Andersen, J	Cell	2011
20795950	NMD: RNA biology meets human genetic medicine Bhuvanagiri, M, Schlitter, AM, Hentze, MW, Kulozik, AE	Biochem J	2010
19010255	NMD: multitasking between mRNA surveillance and modulation of gene expression Neu-Yilik, G, Kulozik, AE	Adv Genet	2008
18524595	The meaning of nonsense Stalder, L, Muhlemann, O	Trends Cell Biol	2008
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