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Intron retention in viruses and cellular genes: Detention, border controls and passports

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Intron retention (IR), where one or more introns remain in the RNA after splicing, was long thought to be rare in mammalian cells, albeit common in plants and some viruses. Largely due to the development of better methods for RNA analysis, it has now been recognized that IR is much more common than previously thought and that this mechanism is likely to play an important role in mammalian gene regulation. To date, most publications and reviews about IR have described the resulting mRNAs as “dead end” products, with no direct consequence for the proteome. However, there are also many reports of mRNAs with retained introns giving rise to alternative protein isoforms. Although this was originally revealed in viral systems, there are now numerous examples of bona fide cellular proteins that are translated from mRNAs with retained introns. These new isoforms have sometimes been shown to have important regulatory functions. In this review, we highlight recent developments in this area and the research on viruses that led the way to the realization of the many ways in which mRNAs with retained introns can be regulated.

This article is categorized under:

  • RNA Processing > Splicing Mechanisms
  • RNA Processing > Splicing Regulation/Alternative Splicing
  • RNA Export and Localization > Nuclear Export/Import
  • RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA elements that mediate the export of mRNAs with retained introns. The HIV RRE promotes the export of unspliced and incompletely spliced HIV mRNAs by interacting with the HIV Rev protein. The initial Rev binding site is circled in red. The MPMV‐CTE promotes the export of MPMV genomic RNA which also serves as the mRNA for the MPMV Gag and GagProPol proteins that are encoded within a retained intron. This element interacts with Nxf1 through the loops circled in red that are identical but rotated 180° relative to each other. The Nxf1 CTE that is found in intron 10 of the NXF1 gene has a single binding site for Nxf1 and promotes the export of an isoform of Nxf1 mRNA that retains intron 10. The regions of the two CTEs shown in the black boxes display high primary sequence identity. The bases shown in red and underlined are identical. These sequences are highly conserved throughout vertebrate evolution
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The fate of detained and retained introns. Detained introns never reach the cytoplasm. mRNAs that contain them may be slowly spliced or spliced in response to a specific signal allowing them to exit the nucleus as a fully spliced mRNA. If they are not spliced they are eventually degraded. However, retained introns can be exported to the cytoplasm through the interaction of an RNA sequence, the CTE, or a CTE‐like element, with cellular export proteins. In the case of the CTE, the cellular export factor is Nxf1. Other, as yet unidentified cellular proteins, may play similar roles through interaction with other CTE‐like elements. This export may be regulated by differential expression of the export proteins in space and time. Once in the cytoplasm, mRNAs with retained introns can have several fates as indicated
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Three mechanisms that promote the export of mRNA with retained introns. (a) Transcription from the HIV provirus produces multiple mRNAs that retain introns and encode different HIV proteins. Their nucleocytoplasmic export is mediated by Rev binding to the RRE, multimerizing and forming a complex with Crm1 and Ran‐GTP which targets them to the nuclear pore for export and subsequent translation in the cytoplasm. (b) Transcription from the MPMV provirus generates an unspliced mRNA that encodes the MPMV Gag and GagProPol proteins within an intron. Export to the cytoplasm is achieved by the binding of Nxf1/Nxt1 to the CTE. In addition to export, Nxf1 is required for efficient translation. (c) The NXF1 gene expresses an alternatively spliced mRNA isoform that retains intron 10, but has spliced out all of the other introns. Similarly to the unspliced MPMV mRNA, it is exported to the cytoplasm by the interaction of a CTE within intron 10 and Nxf1/Nxt1. In the cytoplasm, this mRNA is translated into a truncated Nxf1 (sNxf1) due to a UGA stop codon within the intron. The sNxf1 protein can replace Nxt1 as a cofactor in Nxf1‐mediated export
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RNA Processing > Splicing Mechanisms
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Export and Localization > Nuclear Export/Import
RNA Processing > Splicing Regulation/Alternative Splicing

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