Nonsense-mediated mRNA decay, a simplified view of a complex mechanism

Abstract

Nonsense-mediated mRNA decay (NMD) is both a quality control mechanism and a gene regulation pathway. It has been studied for more than 30 years, with an accumulation of many mechanistic details that have often led to debate and hence to different models of NMD activation, particularly in higher eukaryotes. Two models seem to be opposed, since the first requires intervention of the exon junction complex (EJC) to recruit NMD factors downstream of the premature termination codon (PTC), whereas the second involves an EJC-independent mechanism in which NMD factors concentrate in the 3'UTR to initiate NMD in the presence of a PTC. In this review we describe both models, giving recent molecular details and providing experimental arguments supporting one or the other model. In the end it is certainly possible to imagine that these two mechanisms co-exist, rather than viewing them as mutually exclusive. [BMB Reports 2023; 56(12): 625-632].

Fig. 1

Differences between translation termination at a physiological stop codon (upper panel) and at a premature termination codon (lower panel). When translation stops at a physiological stop codon, the PABPC1 protein recruits eRF1 and helps position it in the A site of the ribosome. When the ribosome pauses on a PTC, PABPC1 is too far away and it’s the UPF3X protein which helps eRF1 to recognize the stop codon, albeit more slowly. This slowdown promotes activation of NMD.

Fig. 2

Degradation pathways activated in NMD. Once the PTC has been recognized, phosphorylated UPF1 will be able to interact with different partners such as the heterodimers SMG5/SMG7 and SMG5/PNRC2. The latter is then capable of activating the decapping complex (DC) in order to remove the 5’ cap bound by the cap binding protein (CBP) that can be CBP80/CBP20 or eIF4E. The heterodimers SMG5/SMG7 can also trigger 3’ deadenylation via the CCR4-NOT complex. Phosphorylated UPF1 can also interact with the SMG6 protein which, through its endonucleolytic activity, induces a cut in the vicinity of the PTC, releasing unprotected 5’ and 3’ ends (upper panel). Exoribonucleases then come into play and degrade the mRNA from the 5’ and 3’ ends generated in the previous step. These degradations involve the XRN1 protein, which has 5’-to-3’ activity, and the exosome, which degrades the RNA in the 3’-to-5’ direction (lower panel).

Fig. 3

(A) The EJC-dependent model. In this model, the EJC recruits the NMD factors UPF3X, UPF2, and then UPF1, which is associated with the translation termination complex (eRF1 and eRF3) and with proteins in charge of its phosphorylation (SMG1/8/9). The recruitment of UPF1 is facilitated by the cap bound by the cap-binding proteins (CPB) (CBP80 and CBP20). This interaction is reinforced by the ARS2 protein. (B) The EJC-independent model. In this model, UPF1 concentrates in the 3’UTR of the mRNA, and the translation termination complex is recruited by the UPF3X protein. The cap is bound by the cap binding protein eIF4E.