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The reciprocal regulation between splicing and 3′‐end processing

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Most eukaryotic precursor mRNAs are subjected to RNA processing events, including 5′‐end capping, splicing and 3′‐end processing. These processing events were historically studied independently; however, since the early 1990s tremendous efforts by many research groups have revealed that these processing factors interact with each other to control each other's functions. U1 snRNP and its components negatively regulate polyadenylation of precursor mRNAs. Importantly, this function is necessary for protecting the integrity of the transcriptome and for regulating gene length and the direction of transcription. In addition, physical and functional interactions occur between splicing factors and 3′‐end processing factors across the last exon. These interactions activate or inhibit splicing and 3′‐end processing depending on the context. Therefore, splicing and 3′‐end processing are reciprocally regulated in many ways through the complex protein–protein interaction network. Although interesting questions remain, future studies will illuminate the molecular mechanisms underlying the reciprocal regulation. WIREs RNA 2016, 7:499–511. doi: 10.1002/wrna.1348 This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3′ End Processing
Schematic representation of mRNA splicing. 5′ ss, 5′ splice site; BPS, branch point sequence; Py, polypyrimidine tract; 3′ ss, 3′ splice site.
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A model for reciprocal regulation between splicing and 3′‐end processing. (a) Transient interaction between splicing factors and 3′‐end processing factors recruits their interacting proteins and stimulates cooperative mRNA processing. (b) Tight and long‐term interaction inhibits enzymatic activity, resulting in inhibition of polyadenylation and degradation.
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U1 snRNP controls the directionality of transcription. The mRNAs from sense‐coding regions have more U1 snRNP‐binding sites and fewer PASs compared with upstream antisense regions. The sense‐coding regions are protected by U1 snRNP, and upstream antisense regions are downregulated by PCPA.
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U1 snRNP inhibits PCPA. Most mammalian genes have cryptic poly(A) sites and U1 snRNP protects pre‐mRNAs from PCPA. The cryptic 5′ splice sites have varying affinities for U1 snRNP, allowing for differential usage of the PAS and cryptic PAS elements. A slight decrease in the relative amount of U1 snRNP causes transcript shortening.
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Viruses control their gene expression using U1 snRNP. (a) The BPV‐1 genome has two potential PASs, the proximal PAS and the distal PAS. (b) U1 snRNP binds to the 5′ splice site‐like sequence located just upstream of the PAS and inhibits polyadenylation, resulting in destabilization of the late genes. (c) HIV has duplicated long terminal repeats (LTRs). Binding of U1 snRNP inhibits cleavage, allowing transcription of the whole genome.
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U1A autoregulates its expression. Two molecules of U1A bind to the 3′ UTR of U1A pre‐mRNA to inhibit PAP activity, resulting in degradation of U1A pre‐mRNA.
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Schematic drawing of 3′‐end processing factors. A[A/U]AUUU, CA, and U/GU rich represent poly(A) signal (PAS), cleavage site, and downstream element (DSE), respectively.
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RNA Processing > Splicing Regulation/Alternative Splicing
RNA Processing > 3′ End Processing

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