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Mutual relationships between transcription and pre‐mRNA processing in the synthesis of mRNA

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Abstract The generation of messenger RNA (mRNA) in eukaryotes is achieved by transcription from the DNA template and pre‐mRNA processing reactions of capping, splicing, and polyadenylation. Although RNA polymerase II (RNAPII) catalyzes the synthesis of pre‐mRNA, it also serves as a principal coordinator of the processing reactions in the course of transcription. In this review, we focus on the interplay between transcription and cotranscriptional pre‐mRNA maturation events, mediated by the recruitment of RNA processing factors to differentially phosphorylated C‐terminal domain of Rbp1, the largest subunit of RNAPII. Furthermore, we highlight the bidirectional nature of the interplay by discussing the impact of RNAPII kinetics on pre‐mRNA processing as well as how the processing events reach back to different phases of gene transcription. WIREs RNA 2013, 4:139–154. doi: 10.1002/wrna.1148 This article is categorized under: RNA Processing > Capping and 5' End Modifications RNA Processing > Splicing Regulation/Alternative Splicing RNA Processing > 3' End Processing

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Transcription elongation rate influences the inclusion of a weak exon into processed mRNA. (a) High elongation rate of RNA polymerase II (RNAPII) results in skipping of the weak exon. Horizontal arrow on the left marks the direction of transcription. Big horizontal arrow above the RNAPII marks high rate by which transcription complex moves along the minigene. Black and green lines represent DNA and nascent mRNA, respectively, and rectangles represent three cassette's exons. The weak exon (magenta) contains exonic splicing enhancer (ESE; red). 3′ Splice sites of this exon and the downstream exon are weak (blue rectangle) and strong (white rectangle), respectively. Serines at positions 2, 5, and 7 (from left to right) of the C‐terminal domain (CTD) heptapeptide repeats are represented as orange (phosphorylated Ser5 or Ser7) or green (phosphorylated Ser2) circles on RNAPII CTD. (b) RNAPII transcribes the minigene with low elongation rate. Therefore, it offers more time for SR proteins to recruit spliceosomal subunits to the weak splice site. Consequently, the weak exon is included into mRNA. Small horizontal arrow above the RNAPII marks low rate by which transcription complex moves along the minigene. Other markings are as above.

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Positive transcription elongation factor b (P‐TEFb) promotes the inclusion of EDA exon into processed mRNA by stimulating the recruitment of SF2/ASF to the elongating RNA polymerase II (RNAPII). (a) Inefficient phosphorylation of RNAPII C‐terminal domain (CTD) at Ser2 residues results in the skipping of EDA exon. Horizontal arrow marks the direction of transcription. Black and green lines represent DNA and nascent mRNA, respectively, and rectangles represent three cassette's exons. EDA exon (magenta) contains exonic splicing enhancer (ESE; red). 3′ Splice sites of EDA and the downstream exon are weak (blue rectangle) and strong (white rectangle), respectively. Serines at positions 2, 5, and 7 (from left to right) of the CTD heptapeptide repeats are represented as white (unphosphorylated), orange (phosphorylated Ser5 or Ser7), or green (phosphorylated Ser2) circles on RNAPII CTD. (b) P‐TEFb stimulates the inclusion of EDA exon via phosphorylation of Ser2 residues of RNAPII CTD. Consequently, splicing activator SF2/ASF is recruited to the CTD and passed on to the ESE, which in turn attracts spliceosomal components for effective pre‐mRNA splicing. Markings are as above.

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CBC (cap‐binding protein complex) stimulates transcription elongation and alternative splicing of pre‐mRNA through the recruitment of positive transcription elongation factor b (P‐TEFb) to transcription complex. Horizontal arrow on the left marks the direction of transcription. Soon after promoter clearance, RNA polymerase II (RNAPII) phosphorylated at Ser5 and Ser7 residues of the C‐terminal domain (CTD) heptapeptide repeats (orange circles) enters into promoter‐proximal pausing because of the actions of the unphosphorylated (white circles) NELF and DSIF (step 1). At this stage, cap (blue box) is synthesized at the 5′ end of pre‐mRNA molecule (green line). Next, CBC binds to the cap, interacts with RNAPII through unknown factor(s) (pink oval with the question mark), and promotes the recruitment of P‐TEFb (curved arrow) for effective phosphorylation of NELF, DSIF, and Ser2 residues of RNAPII CTD (green circles), leading to productive RNAPII elongation (step 2). CBC remains associated with RNAPII throughout transcription, facilitating the presence of P‐TEFb on elongating RNAPII throughout the gene (curved arrow). Consequently, robustly phosphorylated Ser2 residues of RNAPII CTD recruit SR proteins, such as SF2/ASF, which in turn promote pre‐mRNA splicing (step 3). The interaction between the cap‐bound CBC and RNAPII at all times during transcription may result in a dynamic looping of pre‐mRNA (green line).

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Browse by Topic

RNA Processing > Splicing Regulation/Alternative Splicing
RNA Processing > Capping and 5′ End Modifications
RNA Processing > 3′ End Processing

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