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Cross talk between spliceosome and microprocessor defines the fate of pre‐mRNA

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The spliceosome and the microprocessor complex (MPC) are two important processing machineries that act on precursor (pre)‐mRNA. Both cleave the pre‐mRNA to generate spliced mature transcripts and microRNAs (miRNAs), respectively. While spliceosomes identify in a complex manner correct splice sites, MPCs typically target RNA hairpins (pri‐miRNA hairpins). In addition, pre‐mRNA transcripts can contain pri‐miRNA‐like hairpins that are cleaved by the MPC without generating miRNAs. Recent evidence indicates that the position of hairpins on pre‐mRNA, their distance from splice sites, and the relative efficiency of cropping and splicing contribute to determine the fate of a pre‐mRNA. Depending on these factors, a pre‐mRNA can be preferentially used to generate a miRNA, a constitutively or even an alternative spliced transcript. For example, competition between splicing and cropping on splice‐site‐overlapping miRNAs (SO miRNAs) results in alternative spliced isoforms and influences miRNA biogenesis. In several cases, the outcome of a pre‐mRNA transcript and its final handling as miRNA or mRNA substrate can be frequently closely connected to the functional relationships between diverse pre‐mRNA processing events. These events are influenced by both gene context and physiopathological conditions. WIREs RNA 2014, 5:647–658. doi: 10.1002/wrna.1236 This article is categorized under: RNA Processing > 3' End Processing RNA Processing > Processing of Small RNAs RNA Processing > Splicing Regulation/Alternative Splicing

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Canonical splicing signal and auxiliary regulatory elements in precursor (pre)‐mRNA splicing. Correct identification of exonic sequences requires classical 5′ and 3′ splice sites (5′ss and 3′ss) and a series of auxiliary regulatory elements. In the vast majority of splicing events (the so‐called U1–U2 dependent), the 5′ss is composed of the invariant GU dinucleotide surrounded by partially conserved sequences and is recognized by U1 snRNP (U1). The 3′ss contains the AG dinucleotide, the polypyrimidine tract [(Y)n], and the branch point (BP), and interacts with U2 snRNP (U2) and proteins of the U2AF complex. Auxiliary cis‐acting elements [enhancer and silencer, located in the exon (ESE, ESS) and/or in introns (ISE, ISS)] facilitate the exon recognition mainly through direct interaction with trans‐acting factors: the SR proteins act on enhancers and have a positive effect on exon recognition by directly recruiting the splicing factors and/or by antagonizing the action of nearby silencer elements, while hnRNPs mediate splicing inhibition by sterically interfering with other splicing factors or antagonizing SR proteins. Light blue boxes represent the exons and thin line represents the intron. Y indicates pyrimidines, R purine, and N any nucleotide.
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Canonical microRNA (miRNA) biogenesis, processing of primary (pri)‐miRNA‐like hairpins, and fate of cleaved RNAs. Transcription of a coding or noncoding polymerase II gene generates capped and polyadenylated pre‐mRNAs that contain stem–loop structures. In the canonical miRNA biosynthesis, the pri‐miRNA hairpins are cleaved (cropping) by the Drosha/DGCR8 complex (microprocessor complex, MPC) to generate a ∼70‐nt pre‐miRNA, which is recognized by exportin‐5 (Exp‐5). Following the export in the cytoplasm, Dicer catalyzes the second processing step—dicing—to produce a ∼21‐nt miRNA duplex. The miRNA duplex is unwound and one strand (orange) is selected as mature miRNA and incorporated in the RISC complex to function as guide molecule in cleavage or translational repression of target mRNAs, depending on the degree of complementarity between the miRNA and the target genes. The other strand (blue) of the miRNA duplex is degraded. In some cases, pri‐miRNA‐like structures are cleaved by the MPC or by unknown factors but do not produce a miRNA. The cleaved transcripts originated from pri‐miRNA and pri‐miRNA‐like pre‐mRNA can be either degraded in the nucleus or processed to generate normal or alternatively spliced isoforms, which are then exported to the cytoplasm.
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Competition between spliceosome and microprocessor complex (MPC) on splice‐site‐overlapping (SO) microRNAs (miRNAs). The SO miR‐34b and miR‐412 hairpins are located on two different noncoding genes and overlap with corresponding 3′ss: the first is located in the last exon and the second in an internal exon. In miR‐34b, when splicing processing prevails the transcript is preferentially spliced and the mature miR‐34b is not produced. On the contrary, reduction in splicing or preferential recognition of the hairpin by the MPC leads to miR‐34b maturation. In miR‐412, when the central exon is skipped, the MPC crops the pri‐miRNA hairpin, promoting the production of the mature miRNA. On the other hand, when the alternative exon is included, the primary transcript cannot be processed by the MPC and the miRNA is not synthesized. The continuous and dashed lines indicate the processed and unprocessed part of the transcript.
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Genomic location of primary (pri)‐microRNA (miRNA) and pri‐miRNA‐like hairpins. Pri‐miRNA and pri‐miRNA‐like hairpins are located in different positions relative to the splice sites and the gene in both coding and noncoding transcripts. The intronic group contains the intronic hairpins, the mirtrons, and the tailed mirtrons. The exonic group includes hairpins located in the central exons and in the 5′ and 3′ UTRs (or in corresponding first and terminal exons for noncoding transcripts). In splice‐site overlapping (SO), the hairpins overlap with 5′ or 3′ splice sites. Blue boxes represent the exons, thin lines the introns, and thick lines the 5′ or 3′ UTRs.
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miR‐34b/c transcript and miR‐34b secondary structure. BC021736 is the noncoding transcript that contains the pri‐miR‐34b and pri‐miR‐34c. The zoomed image of splice‐site‐overlapping (SO) miR‐34b secondary structure shows the elements involved in splicing regulation: the AG dinucleotide of the 3′ss, which is embedded in the hairpin, the branch point (BP) consensus, and the downstream 9‐bp purine‐rich exonic enhancer (ESE). The mature form of the miRNA is shown in orange. Blue boxes and thin line represent exons and intron, respectively. The black arrow indicates the promoter and TSS is the transcription start site.
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Cropping of a primary (pri)‐microRNA (miRNA) hairpin in the 3′ UTR of FSTL1 regulates keratinocytes proliferation/migration. Pri‐miR‐198 is located in the 3′ UTR of the follistatin‐like 1 (FSTL1), a protein involved in keratinocytes migration. In normal keratinocytes, binding of KSRP (K‐homology splicing regulatory protein) to the terminal loop of the hairpin promotes microprocessor complex (MPC)‐dependent cropping of miR‐198 that in turn downregulates the expression of promigratory protein targets (DIAPH1, PLAU, and LAMC2). After injury, a series of events induced by Transforming growth factor ‐ β (TGF‐β) result in downregulation of KSRP and inhibition of MPC‐dependent cleavage. This reduces the amount of miR‐198 and activates promigratory proteins. In parallel, the expression of FSTL1 protein is increased. Gray boxes indicate 5′ and 3′ UTR regions; white boxes and thin line represent exons and introns, respectively.
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RNA Processing > Processing of Small RNAs
RNA Processing > Splicing Regulation/Alternative Splicing
RNA Processing > 3′ End Processing

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