Exon–exon junction – what's your function?

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The expression of aberrant proteins can have disastrous consequences for a cell. Quality-control mechanisms that survey newly synthesized mRNAs are therefore essential to cellular well being. Unspliced pre-mRNAs are retained in the nucleus because they fail to associate with the appropriate export factors. Another quality-control measure operates in the cytoplasm, where mRNAs containing premature termination codons are degraded via the nonsense-mediated mRNA decay (NMD) pathway. In a prime example of complementary work from multiple laboratories, three recent papers have coordinately reported a central role for the multiprotein exon–exon junction complex (EJC) in coordinating these mRNA-surveillance mechanisms1xThe exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. Le Hir, H. et al. EMBO J. 2001; 17: 4987–4997Crossref | Scopus (442)See all References, 2xCommunication of the position of exon–exon junctions to the mRNA surveillance machinery by the protein RNPS1. Lykke-Andersen, J. et al. Science. 2001; 293: 1836–1839Crossref | PubMed | Scopus (255)See all References, 3xRole of the nonsense-mediated decay factor hUfp3 in the splicing-dependent exon–exon junction complex. Kim, V.N. et al. Science. 2001; 293: 1832–1836Crossref | PubMed | Scopus (209)See all References.When an intron is spliced out of a pre-mRNA molecule, the EJC is deposited approximately 20 nucleotides upstream of the resulting exon–exon junction, establishing a positional marker on the mRNA. Inside the nucleus, the EJC consists of at least five proteins, but, as these papers report, it might better be thought of as a ‘dynamic post-splicing complex2xCommunication of the position of exon–exon junctions to the mRNA surveillance machinery by the protein RNPS1. Lykke-Andersen, J. et al. Science. 2001; 293: 1836–1839Crossref | PubMed | Scopus (255)See all References2’ that evolves along the mRNA processing pathway rather than being a static landmark.Moore and colleagues1xThe exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. Le Hir, H. et al. EMBO J. 2001; 17: 4987–4997Crossref | Scopus (442)See all References1 engineered a pre-mRNA molecule with a very short (<20 nucleotide) 5′ exon that was efficiently spliced but failed to provide a docking site for the EJC. Using this mRNA, they demonstrated that the EJC is crucial for efficient nuclear export of spliced mRNAs. It performs this role through an interaction between the EJC component REF and the mRNA export factor TAP/p15. In the cytoplasm, REF and TAP/p15 dissociate from the mRNA, whereas other EJC proteins remain bound and go on to function in co-translational NMD. By artificially tethering EJC components to the 3′UTRs of β-globin mRNAs, Steitz and colleagues2xCommunication of the position of exon–exon junctions to the mRNA surveillance machinery by the protein RNPS1. Lykke-Andersen, J. et al. Science. 2001; 293: 1836–1839Crossref | PubMed | Scopus (255)See all References2 identified the protein RNPS1 as a key factor in NMD and also documented a somewhat lesser role for the protein Y14. The association of RNPS1 and Y14 with NMD seems to mediated through their interaction with the Upf3 protein2xCommunication of the position of exon–exon junctions to the mRNA surveillance machinery by the protein RNPS1. Lykke-Andersen, J. et al. Science. 2001; 293: 1836–1839Crossref | PubMed | Scopus (255)See all References, 3xRole of the nonsense-mediated decay factor hUfp3 in the splicing-dependent exon–exon junction complex. Kim, V.N. et al. Science. 2001; 293: 1832–1836Crossref | PubMed | Scopus (209)See all References, which Dreyfuss and coworkers show joins the EJC in the nuclear compartment3xRole of the nonsense-mediated decay factor hUfp3 in the splicing-dependent exon–exon junction complex. Kim, V.N. et al. Science. 2001; 293: 1832–1836Crossref | PubMed | Scopus (209)See all References3. According to the current model of NMD, if, during the first round of translation, a termination codon is encountered upstream of the Upf3-marked EJC, NMD is initiated with the cooperation of the other NMD proteins Upf1 and Upf2.In summary, these three papers have made significant progress towards understanding the integrative function of the EJC as an essential component of mRNA quality control and defining the dynamic cast of characters that make up the quality-control machinery. Further studies will elucidate the still-unknown mechanism by which the EJC is deposited on mRNA and the precise mRNA–protein and protein–protein interactions that enable its proper function.