Nonsense-mediated mRNA Decay

When an mRNA molecule is transported from the nucleus to the cytosol, as its 5ʹ end emerges from a nuclear pore, a ribosome begins to translate it.  This test translation checks the mRNA for errors and flags irregularly processed mRNAs for degradation. In this mRNA surveillance mechanism, called the nonsense-mediated mRNA decay pathway, or NMD, the ribosome can detect if an mRNA molecule has a nonsense or stop codon in the wrong place. Generally, a pre-mRNA can contain stop codons within introns, in addition to the intended stop codon. When this pre-mRNA is spliced and processed in the nucleus, exon junction complexes, or EJCs, bind the mRNA at each splice site. In the test round of translation, the EJCs are displaced by the moving ribosome.  In a normally spliced mRNA, the stop codon, marked by the sequence UAA, UAG or UGA, lies within the last exon. So, when the ribosome reaches it and the translation is terminated, there are no bound EJCs.   Such an mRNA passes the quality check and is now available for further rounds of translation. Incompletely spliced mRNAs still have nonsense codons present in the reading frame of the mRNA. This phenomenon is observed more frequently in organisms with longer introns. As a ribosome translates this mRNA, it reaches a stop codon, before interacting with the final EJC. The stalled ribosome terminates the translation prematurely while the pathway activates the NMD response. The bound EJC serves as a binding platform for NMD factors including Up-frameshift proteins, Upf1, Upf2, and Upf3, and a phosphorylating enzyme SMG. These proteins recruit exonucleases that degrade the faulty mRNA. NMD surveillance is critical in selecting for genetic combinations that can produce a functional protein.