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What is the switch for coupling transcription and splicing? RNA Polymerase II C‐terminal domain phosphorylation, phase separation and beyond

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Abstract Phosphorylation of the RNA polymerase II C‐terminal domain (Pol II CTD) has important roles in the kinetic coupling of splicing with transcription, which is essential for many genes to maintain correct splicing patterns. However, because of the extensively repeated low complexity sequences of Pol II CTD, it was unclear how phosphorylation‐dependent molecular interactions were able to provide sufficient specificity to spatiotemporally partition various cotranscriptional events. Here we try to view the molecular mechanisms governing cotranscriptional splicing from the role of phase separation based on recent studies showing the ability of Pol II CTD to form droplets. This article is categorized under:   RNA Processing > Splicing Regulation/Alternative Splicing   RNA Processing > Splicing Mechanisms   RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
Schematic of the spliceosome assembly pathway. (Left) Assembly model based on “intron definition”. U1 and U2 small nuclear ribonucleoprotein (snRNP) first recognize both ends of an intron. (Right) Assembly by the “exon definition” model is superimposed on a cartoon of elongating Pol II. The exonic region of nascent RNA is tethered on polymerase II C‐terminal domain by U1 and U2 snRNPs. Nucleosomes often contain exonic regions, and the reduction of elongation rates at the nucleosome may induce deposition of both U1 and U2 snRNP on exon ends leading to tethering of the exon. At this time, the direction of U1 and U2 is opposite to the intron definition model. This complex further accepts tri‐snRNP to form a B‐like complex that can be converted to a catalytically active spliceosome when paired to the upstream or downstream exon
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Schematic of two possible circRNA formation pathways. Circular RNA (circRNA) formation occurs in independent pathways. In model A, a cis‐element and an RNA‐binding protein cause incorrect spliceosome assembly. In model B, re‐splicing of lariat introns containing skipped exons causes back splicing
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Schematic of recursive splicing. Recursive splicing (RS) is divided into two steps. The RS exon is important in the first step but is removed at the second. RS exons have several features compared with canonical exons
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C‐terminal domain (CTD) undergoes phosphorylation‐dependent loose separation in nuclear speckles. Polymerase II (Pol II) may be incorporated into droplets depending on its phosphorylation levels. If Ser5 is highly phosphorylated, the droplet in which CTD is incorporated preferentially recruits spliceosome factors compared with other processing factors. In the paused state, less‐phosphorylated Pol II may be trapped in U1 and FUS‐enriched droplets which protect nascent RNA. Nuclear speckles store many RNA‐binding proteins so spliced RNA and released transcripts containing an intron may be tethered deep inside nuclear speckles until export
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Depiction of independent droplet formation by phosphorylated and unphosphorylated C‐terminal domain (CTD). Phosphorylation of CTD triggers its movement to different classes of phase separated droplets
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Comparison of spliceosome factors detected in the S5P complex or nuclear speckles. Gray boxes indicate that the protein is in the list. Proteins colored by light green or orange are specifically listed in nuclear speckles or S5P complex, respectively. The classification of spliceosome factors is according to Funnell et al. ()
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RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Processing > Splicing Mechanisms
RNA Processing > Splicing Regulation/Alternative Splicing

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