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ALREX‐elements and introns: two identity elements that promote mRNA nuclear export

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The mechanisms that dictate whether a particular mRNA is exported from the nucleus are still poorly defined. However, it has become increasingly clear that these mechanisms act to promote the expression of protein‐coding mRNAs over the high levels of spurious transcription that is endemic to most eukaryotic genomes. For example, mRNA processing events that are associated with protein‐coding transcripts, such as splicing, act as mRNA identity elements that promote nuclear export of these transcripts. Six years ago, we made the serendipitous discovery that regions within the open reading frame of an mRNA that encode short secretory or mitochondrial‐targeting peptides can also act as an mRNA identity element which promotes an alternative mRNA nuclear export (ALREX) pathway. These regions are enriched in protein coding genes and have particular features that can be used to identify this class of protein‐coding mRNA. In this article we review our current knowledge of how mRNA export evolved in response to particular events that occurred at the base of the eukaryotic tree. We will then focus on our current understanding of ALREX and compare its features to splicing‐dependent export, the main mRNA export pathway in metazoans. WIREs RNA 2013, 4:523–533. 10.1002/wrna.1176 This article is categorized under: RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Export and Localization > Nuclear Export/Import

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A General model for splicing‐ and ALREX‐regulated events. During transcription, the first element to emerge from RNA Polymerase II dictates which export pathway is utilized by any given transcript. In splicing‐dependent export, the nuclear cap binding complex and the spliceosome collaborate to deposit the TREX complex near the 5′end of the transcript. In addition the spliceosome also deposits the EJC upstream of most exon–exon junctions. SSCRs and MSCRs that are present in the first exon of human genes contain features that are associated with ALREX. It remains unclear what factors are recruited to these ALREX‐promoting elements; however, it is likely that these elements help to load the TREX complex onto the mRNA, perhaps in collaboration with the nuclear cap binding complex. In addition it is possible that these elements, in collaboration with the spliceosome, help to either recruit or modify the composition of the EJC.
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A model for the potentiation of translation of ALREX‐mRNA by RanBP2/Nup358. Upon the completion of export, ALREX‐elements interact with the zinc finger repeats of RanBP2. This interaction promotes the efficient translation of these mRNAs by an unknown mechanism. It is possible that RanBP2 may modify EJC components, nuclear factors that bind ALREX‐elements, or translation initiation factors. Alternatively RanBP2 may help deliver mRNAs to the translocon, which mediates the insertion of secretory proteins into the ER‐lumen. The interaction between RanBP2 and ALREX elements may be regulated by Ran. Mutations in ALREX‐elements, or depletion of RanBP2, cause these mRNAs to be inefficiently translated and targeted to stress granules instead of the ER.
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Codon bias in human signal sequence coding regions. (a) Hydrophobic amino acids tend to contain uracil at their second coding position. For every amino acid (x‐axis), hydrophobicity was plotted, as measured by the Gibbs free energy associated with the apparent membrane partitioning of a model transmembrane domain that contained that amino acid at a defined position (ΔG app, y‐axis). Amino acids were color‐coded based on the nucleotide found at the second coding position. For example, all of the isoleucine codons (AUC, AUU, AUA) contain a uracil at the second coding position. Note that for serine, four of its codons contain a C, and two contain a G at the second position. (b) Amino acids that are enriched in human signal sequences tend to have few adenines in their codons. For every amino acid, the average number of adenines per codon (y‐axis), adjusted for codon usage within the human genome, was plotted against hydrophobicity (x‐axis). For amino acids with similar hydrophobicities, there is a bias in human SSCRs against those with relative high adenine content (isoleucine, methionine, and lysine indicated in red) for those with low adenine content (leucine, cysteine, and arginine in green).
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RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution
RNA Export and Localization > Nuclear Export/Import
RNA Export and Localization

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