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The significant other: splicing by the minor spliceosome

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Abstract The removal of non‐coding sequences, introns, from the mRNA precursors is an essential step in eukaryotic gene expression. U12‐type introns are a minor subgroup of introns, distinct from the major or U2‐type introns. U12‐type introns are present in most eukaryotes but only account for less than 0.5% of all introns in any given genome. They are processed by a specific U12‐dependent spliceosome, which is similar to, but distinct from, the major spliceosome. U12‐type introns are spliced somewhat less efficiently than the major introns, and it is believed that this limits the expression of the genes containing such introns. Recent findings on the role of U12‐dependent splicing in development and human disease have shown that it can also affect multiple cellular processes not directly related to the functions of the host genes of U12‐type introns. At the same time, advances in understanding the regulation and phylogenetic distribution of the minor spliceosome are starting to shed light on how the U12‐type introns and the minor spliceosome may have evolved. WIREs RNA 2013, 4:61–76. doi: 10.1002/wrna.1141 This article is categorized under: RNA Processing > Splicing Mechanisms

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Consensus sequences of human U12‐ and U2‐type introns. The height of the letters in each position indicates the relative frequency of individual nucleotides in that position. For frequency calculation the U12‐type splice site sequences were obtained from U12DB,7 and the corresponding 5′ss and 3′ss frequencies for U2‐type introns from the Splice Rack database (Ref 8; http://katahdin.mssm.edu/splice/index.cgi?database=spliceNew2) and the branch point sequences (BPS) data from Gao et al.,9 The sequence logos were generated using the enoLOGOS web server.10

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Exon definition interactions and regulation of U12‐type factors by alternative splicing nonsense‐mediated decay (AS‐NMD). (a) Exon definition interactions form between U2‐ and U12‐dependent spliceosomes in both the upstream and downstream direction, aided by SR protein interactions.77,80 Intron bridging differs in U12‐dependent splicing as a consequence of the cooperative recognition by the U11/U12 di‐snRNP.47 (b) The di‐snRNP activates alternative splicing by binding to the U11 snRNP‐binding splicing enhancer (USSE) element in the U11‐48K and U11/U12‐65K transcripts and recruits U2‐type splicing factors to the upstream 3′ss. Alternatively spliced products are degraded.81

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RNA–RNA interactions in the catalytic cores of the minor and major spliceosomes. Interactions between snRNAs and the 5′ss or BPS are indicated by cyan shading. U2/U6 or U12/U6atac interactions are indicated by green (helix I), purple (helix II), and yellow shading (helix III), as in Figure 4. The minor spliceosome structure is based on data published in Ref 59. The U12/U6atac helix III structure is controversial as it is not conserved in plants,67 but mutations in U12 snRNA that weaken this structure reduce the splicing activity in mammals.35

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The predicted secondary structures of the human spliceosomal snRNAs. The binding sites for Sm proteins are shaded in gray, and the sequences interacting with the 5′ss or BPS in cyan. Sequences involved in various U2/U6 or U12/U6atac interactions are indicated by green (helix I), purple (helix II), and yellow shading (helix III), similar to Figure 5. Nucleotide modifications are omitted. (Structures are based on data originally published in Ref 34 for U1, U2, and U5, Ref 18 for U11, Ref 35 for U12, and Ref 29 for U4, U6, U4atac, and U6atac). The locations and identities of the Taybi‐Linder syndrome or microcephalic osteodysplastic primordial dwarfism type I (TALS/MOPD1) mutations in the U4atac snRNA are from Ref 36 and are indicated in red.

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Spliceosome assembly. The interactions of the spliceosomal snRNPs and some selected non‐snRNP protein complexes at various stages of spliceosome assembly (complexes E, A, B*, and C) are depicted schematically for both the U2‐ and U12‐dependent spliceosomes. The Prp19/CDC5 complex is indicated by ‘19C’. Its association with the U12‐dependent spliceosome is inferred from the major spliceosome and is therefore indicated with a question mark. (Adapted with permission from Ref 27. Copyright 2003 Macmillan Publishers Ltd)

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Phylogenetic distribution of U12‐type introns and splicing factors, with special emphasis on the recurrent loss of U12‐dependent splicing in the fungi‐metazoa lineage. Filled circles in the schematic tree indicate taxa in which U12‐type introns and/or splicing factors have been identified, while open circles indicate taxa in which they have not been observed. Names of individual genera have been given in italics. The lengths of the branches do not indicate true phylogenetic distances. The tree is based on the data obtained from Refs 19 and 23.

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