Nonsense-Mediated mRNA Decay, a Finely Regulated Mechanism

Abstract

Nonsense-mediated mRNA decay (NMD) is both a mechanism for rapidly eliminating mRNAs carrying a premature termination codon and a pathway that regulates many genes. This implies that NMD must be subject to regulation in order to allow, under certain physiological conditions, the expression of genes that are normally repressed by NMD. Therapeutically, it might be interesting to express certain NMD-repressed genes or to allow the synthesis of functional truncated proteins. Developing such approaches will require a good understanding of NMD regulation. This review describes the different levels of this regulation in human cells.

Keywords: UPF proteins; gene expression; nonsense-mediated mRNA decay; regulation; therapeutic perspectives.

Figure 1

Rules for eliciting NMD according to the two models of NMD activation in human cells. (A) The EJC-dependent model. During the first round of translation (or the pioneer round of translation) when the CBP20 (20) -CBP80 heterodimer is present on the cap at the 5′ end and the PABPC1 and PABPN1 proteins are bound to the poly (A) tail at the 3′ end, a stop codon is recognized as a PTC if it is located more than 50 to 55 nucleotides upstream of an exon-exon junction. The presence of an EJC (exon junction complex) 20 to 24 nucleotides upstream of the exon-exon junction leads to recruitment of NMD factors when the ribosome reaches the PTC. Then NMD is activated and this mRNA is degraded; (B) The EJC-independent model. In this model, the distance between the first stop codon encountered by the ribosome and the PABPC1 determines whether this stop codon is premature or not.

Figure 2

Examples of natural NMD substrates. Topmost example: Presence of a small open reading frame upstream of the main open reading frame. If the ribosome reads this small open reading frame, the stop codon of this ORF is recognized as a PTC because of the presence of downstream exon-exon junctions. Consequently, NMD of this mRNA is activated. If the ribosome reads the main open reading frame, no PTC is detected on this mRNA and its degradation through NMD is not activated. Second example: Part of the 3’UTR is removed by splicing. This splicing event results in EJC deposition 20–24 nucleotides upstream of the splicing event and hence in recognition of the physiological stop codon as a PTC if the splicing event is located more than 50–55 nucleotides downstream of the physiological stop codon. Third example: Changes in the splicing profile of a pre-mRNA lead, for example, to intron retention or exon skipping. These events very often lead to introduction of a PTC and hence to activation of NMD of this mRNA. Example four: In mRNAs having a long to very long 3′UTR, the physiological stop codon is recognized as a PTC and NMD of this mRNA is activated. Bottom-most example: mRNAs encoding selenoproteins. Selenocysteine is encoded by the UGA nucleotide triplet. In the presence of selenium and when located in a particular context allowing its recognition as the codon encoding selenocysteine, this UGA leads to synthesis of a selenoprotein. In the absence of selenium, the UGA is recognized as a stop codon and NMD of this mRNA is activated.