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  • Review Article
  • Published:

Coupling mRNA processing with transcription in time and space

Nature Reviews Genetics volume 15, pages 163–175 (2014)Cite this article

Subjects

Key Points

  • Maturation of pre-mRNA by capping, splicing, and cleavage and polyadenylation can occur co-transcriptionally at the gene; the substrate for these reactions is therefore a growing nascent RNA chain. Recent high-throughput sequencing of nascent RNA chains that are caught in the act of being synthesized shows that a large proportion of all splicing events occur co-transcriptionally.

  • Pre-mRNA processing is spatiotemporally coordinated with transcription by recruitment and kinetic coupling mechanisms, which facilitate binding of processing factors to the transcription elongation complex (TEC) and coordinate the rates of nascent RNA processing with transcription elongation.

  • Transcription elongation rate varies both between genes and between regions within a gene and can affect the outcomes of alternative splicing and alternative polyadenylation decisions. An important open question is whether elongation rate is regulated to effect changes in alternative mRNA processing.

  • Slow elongation lengthens the 'window of opportunity' for an upstream event to occur before it faces competition from a downstream RNA sequence element; conversely, fast elongation 'closes' that window of opportunity.

  • Recruitment of processing factors is mediated through contacts with the nascent RNA and protein surfaces on the TEC, most notably the carboxy-terminal domain (CTD) of RNA polymerase II that functions as a flexible and versatile 'landing pad'. Interfaces between the CTD and several binding proteins are known at atomic resolution.

  • Dynamic changes in the phosphorylation state of the CTD are synchronized with the cycle of transcription initiation, elongation and termination, and help to direct the traffic of processing factors on and off the landing pad.

  • Recent discoveries indicate a new class of regulators of mRNA production that target the kinetic coupling mechanism by influencing transcription elongation rate and splicing.

Abstract

Maturation of mRNA precursors often occurs simultaneously with their synthesis by RNA polymerase II (Pol II). The co-transcriptional nature of mRNA processing has permitted the evolution of coupling mechanisms that coordinate transcription with mRNA capping, splicing, editing and 3′ end formation. Recent experiments using sophisticated new methods for analysis of nascent RNA have provided important insights into the relative amount of co-transcriptional and post-transcriptional processing, the relationship between mRNA elongation and processing, and the role of the Pol II carboxy-terminal domain (CTD) in regulating these processes.

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Figure 1: The major co-transcriptional mRNA processing steps.
Figure 2: The co-transcriptional nature of pre-mRNA processing.
Figure 3: The carboxy-terminal domain 'landing pad' of RNA polymerase II.
Figure 4: Kinetic coupling of transcription with folding and processing of the pre-mRNA.
Figure 5: Global co-transcriptional splicing detected by deep sequencing of nascent RNA.

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Acknowledgements

The author apologizes to colleagues whose work was not referenced because of space limitations. Work in D.L.B's laboratory is supported by the US National Institutes of Health grants GM58163 and GM063873. The author thanks Y. Shav-Tal, D. Licatalosi, T. Blumenthal, R. Davis, D. Ish-Horowitz and members of his laboratory for discussions, and K. A. Nasmyth, J. Cooper and Cancer Research UK for their hospitality during preparation of the manuscript.

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    David L. Bentley

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Glossary

Carboxy-terminal domain

(CTD). Located in the large subunit of RNA polymerase II, the CTD is a signature feature of this polymerase that contains conserved heptad repeats (52 YSPTSPS repeats in humans) and is not found in RNA polymerases I and III.

Transcription elongation complex

(TEC). A complex of RNA polymerase that is stably bound to the DNA template, polymerase-bound proteins and the nascent RNA chain.

Alternative splicing

The most important mechanism by which the transcriptome is diversified through production of multiple mRNAs from a single gene. Alternatively spliced mRNAs differ in their coding and non-coding sequences as a result of selective inclusion and exclusion of exon and intron sequences.

Transcription start site

The site on the DNA where the first phosphodiester bond in a RNA transcript is formed.

Commitment complex

A stable complex formed between an intron-containing pre-mRNA, the U1 small nuclear ribonucleoprotein particle bound to the 5′ splice site, branch point-binding protein bound to the branch point and U2 auxiliary factor bound to the 3′ splice site. Once formed, it remains committed to the completion of splicing even when challenged with an excess of pre-mRNA substrate.

R-loops

Structures that are formed by the hybridization of RNA transcripts to double-stranded DNA in which the displaced non-template DNA strands are looped out. Their recombinogenic nature causes genomic instability.

Alternative polyadenylation

The decision to process at one of multiple poly(A) sites that are present at the 3′ ends of most human genes. This decision can have important functional consequences because it determines the sequence content of the 3′ untranslated region, which controls mRNA stability and translational efficiency.

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Bentley, D. Coupling mRNA processing with transcription in time and space. Nat Rev Genet 15, 163–175 (2014). https://doi.org/10.1038/nrg3662

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