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Splicing and transcription touch base: co-transcriptional spliceosome assembly and function

Key Points

  • Splicing mainly takes place during transcription. Catalysis is achieved through the stepwise assembly of the spliceosome onto nascent RNA.

  • Recent in vivo studies have shown that the catalytic spliceosome is physically close to RNA polymerase II, underscoring that spliceosome assembly and splicing catalysis occur on similar timescales to transcription.

  • Transcription elongation rate and pausing influence splice site availability and consequent spliceosome assembly. DNA sequence, nucleosome positioning, chromatin structure and post-translational modifications of the RNA polymerase II carboxy-terminal domain influence transcription dynamics.

  • Splicing is coupled to other pre-mRNA processing events, such as 5′ end capping, 3′ end processing and RNA editing, thereby ensuring the efficient and precise production of mature mRNAs.

  • Efficient co-transcriptional processing of nascent RNA may be achieved by concentrating transcription and processing machineries in subnuclear membrane-less compartments.

Abstract

Several macromolecular machines collaborate to produce eukaryotic messenger RNA. RNA polymerase II (Pol II) translocates along genes that are up to millions of base pairs in length and generates a flexible RNA copy of the DNA template. This nascent RNA harbours introns that are removed by the spliceosome, which is a megadalton ribonucleoprotein complex that positions the distant ends of the intron into its catalytic centre. Emerging evidence that the catalytic spliceosome is physically close to Pol II in vivo implies that transcription and splicing occur on similar timescales and that the transcription and splicing machineries may be spatially constrained. In this Review, we discuss aspects of spliceosome assembly, transcription elongation and other co-transcriptional events that allow the temporal coordination of co-transcriptional splicing.

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Figure 1: Yeast gene architecture and co-transcriptional spliceosome assembly.
Figure 2: Crosstalk of the assembling spliceosome with nuclear gene expression machineries.
Figure 3: Patterns of RNA polymerase II C-terminal domain phosphorylation, small nuclear ribonucleoprotein binding and splicing along an average intron-containing budding yeast gene.
Figure 4: Gene architecture, chromatin features and nascent RNA properties influence co-transcriptional splicing.
Figure 5: First, internal and terminal exon definition.
Figure 6: Higher-order organization of the gene expression machineries.

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Acknowledgements

The authors are grateful to H. Herzel and K. Reimer for comments on the manuscript. This work was supported in part by NIH R01GM112766 from the National Institute of General Medical Sciences (to K.M.N.) and by T32GM007223 (to T.A.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the US National Institutes of Health.

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Glossary

5′ end capping

The addition of an untemplated guanosine to the 5′ end of an RNA polymerase II transcript followed by its methylation at the N7 position. Capping protects the mRNA 5′ end from endonucleases.

3′ end cleavage and polyadenylation

Endonucleolytic cleavage that defines the 3′ ends of RNA polymerase II transcripts by cleavage and polyadenylation specificity factor (CPSF) and other factors, followed by the addition of non-templated poly(A) tails by poly(A) polymerase.

Nascent RNA

RNA that is tethered to DNA by any elongating RNA polymerase.

Gene architecture

The ensemble of cis-regulatory, coding and non-coding elements of a gene, including length, position and sequence.

Ultraviolet (UV) crosslinking

UV irradiation-induced covalent bonds that link amino acids with nucleic acids.

SR proteins

RNA-binding proteins with long repeats of arginine (Arg) and serine (Ser) residues that are involved in the regulation of alternative splicing and other steps of gene expression.

Intrinsically disordered regions

Protein regions that contain little amino acid diversity and appear to lack well-defined secondary and tertiary structures.

Speckles

Membrane-less subnuclear granules that are enriched in splicing factors, particularly the SR proteins.

Cajal bodies

Membrane-less subnuclear compartments (2–4 per cell) that are the sites of small nuclear RNA modification and small nuclear ribonucleoprotein assembly. Cajal bodies are not the sites of splicing.

P-bodies

Membrane-less cytoplasmic compartments that are involved in mRNA turnover.

Lampbrush chromosomes

Giant meiotic chromosomes that are formed in oocyte nuclei owing to the looping of chromosomal regions that are highly transcribed and coated with nascent RNA.

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Herzel, L., Ottoz, D., Alpert, T. et al. Splicing and transcription touch base: co-transcriptional spliceosome assembly and function. Nat Rev Mol Cell Biol 18, 637–650 (2017). https://doi.org/10.1038/nrm.2017.63

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