Mechanism and regulation of the nonsense-mediated decay pathway

Abstract

The Nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs) but also regulates the abundance of a large number of cellular RNAs. The central role of NMD in the control of gene expression requires the existence of buffering mechanisms that tightly regulate the magnitude of this pathway. Here, we will focus on the mechanism of NMD with an emphasis on the role of RNA helicases in the transition from NMD complexes that recognize a PTC to those that promote mRNA decay. We will also review recent strategies aimed at uncovering novel trans-acting factors and their functional role in the NMD pathway. Finally, we will describe recent progress in the study of the physiological role of the NMD response.

Figure 1.

Dual role of the Nonsense-mediated decay (NMD) pathway. NMD degrades PTC-containing transcripts (‘faulty’ transcripts) (top panel) and also regulates the expression of naturally occurring transcripts (‘normal transcripts’), acting as a fine-tuning mechanism of gene expression (bottom panel). Green spheres represent both ribosomal subunits, whereas red circles depict the core NMD factor, UPF1.

Figure 2.

Mechanism of NMD activation in mammalian cells, indicating the transition from the surveillance complex (SURF) to the decay-inducing complex (DECID). UPF1 and its associated kinase, SMG1, bind to the eukaryotic release factors eRF1 and eRF3 to form the SURF complex in the vicinity of a premature termination codon (PTC). A subsequent interaction of this complex with UPF2, UPF3b and an exon junction complex (EJC) downstream of the PTC triggers the formation of the DECID complex, resulting in UPF1 phosphorylation and release of eRF1 and eRF3. Phosphorylated UPF1 acts to recruit SMG5, SMG6 and SMG7, and general mRNA degradation factors that lead to mRNA degradation.

Figure 3.

Role of RNA helicases in NMD. (A) The exon junction complex (EJC) component, eIF4AIII, nucleates NMD factors, promoting interactions with UPF2 and UPF3b. (B) RuvBL proteins promote activation of the SMG1 kinase during initial stages of NMD (upper panel). DHX34 promotes the transition from the SURF to DECID complex (lower panel). (C) Function of the RNA helicases UPF1 and MOV10 in mRNP clearance.

Figure 4.

NMD factors in yeast, nematodes and humans, indicating the method by which they were first identified.