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Prp40 and early events in splice site definition

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The alternative splicing (AS) of precursor messenger RNA (pre‐mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ligated. The AS of pre‐mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active‐site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre‐mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. WIREs RNA 2016, 7:17–32. doi: 10.1002/wrna.1312 This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing
Schematic representation of spliceosome assembly and pre‐messenger RNA splicing. The first step in spliceosome assembly is the formation of complex E, also called the commitment complex. The 5′ splice site (GU, 5′ SS) is bound by the U1 small nuclear ribonucleoprotein (snRNP), and the splicing factors SF1/BBP and U2AF cooperatively recognize the branch point sequence (BPS), the polypyrimidine (Py) tract, and the 3′ splice site (AG, 3′ SS). The pairing of the U2 snRNP with the BPS in an ATP‐dependent manner results in the prespliceosomal complex A. Subsequent steps lead to the binding of the U4/U5–U6 tri‐snRNP and the formation of complex B. The catalytic complex C, which catalyzes two transesterification reactions at the splice sites, is formed after rearrangements that detach the U1 and U4 snRNPs. Complex C undergoes additional rearrangements that result in the excision of the intron, which is removed as the lariat RNA, and ligation of the exons. The U2, U5, and U6 snRNPs are then released from the particle and recycled for subsequent rounds of splicing.
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Molecular phylogenetic analysis of the PRP40 family using the maximum likelihood method. The evolutionary history was inferred using the maximum likelihood method. The bootstrap consensus tree inferred from 500 replicates is considered to represent the evolutionary history of the analyzed taxa. Branches corresponding to partitions reproduced in less than 50% of the bootstrap replicates were collapsed. The black circles represent mammalian clades.
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Protein sequence alignment of PRPF40A and PRPF40B. Identical amino acids are indicated with an asterisk (*), whereas those that show a high degree of similarity are indicated with a colon (:), and those that show less similarity are marked with a dot (·). The orange boxes indicate the predicted sequences corresponding to the WW domains, and the blue boxes indicate the predicted sequences corresponding to the FF domains.
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Schematic representation of proteins with WW and FF domains that are predicted to play dual roles in both transcription and splicing (see text). yPrp40, yeast Prp40; hPRPF40A and hPRPF40B, human PRPF40A and PRPF40B, respectively; hTCERG1, human TCERG1. The WW and FF domains are depicted in purple and blue, respectively.
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Alternative splicing (AS) regulation by cis‐elements and trans‐acting factors. The core cis sequence elements that define the exon/intron boundaries (5′ and 3′ splice sites, GU–AG) and associated 3′ sequences [polypyrimidine (Py) tract and branch point (A) sequence] are poorly conserved. Additional enhancer and silencer elements in exons and in introns (ESE, exonic splicing enhancers; ESI, exonic splicing silencers; ISE, intronic splicing enhancers; ISI, intronic splicing silencers) add another layer of AS regulation. Trans‐acting splicing factors, e.g., SR family proteins and heterogeneous nuclear ribonucleoprotein particles (hnRNPs), bind to enhancers and silencers and interact with spliceosomal components. In general, SR proteins bound to enhancers facilitate exon recognition (red arrows), and hnRNPs inhibit this process (black arrows).
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RNA Processing > Splicing Regulation/Alternative Splicing

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