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The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain

Nature Reviews Molecular Cell Biology volume 18, pages 263–273 (2017)Cite this article

Subjects

Key Points

  • The carboxy-terminal domain (CTD) of RNA polymerase II (Pol II) is composed of repeats of the heptapeptide Tyr-Ser-Pro-Thr-Ser-Pro-Ser and is dynamically post-translationally modified to regulate transcription.

  • CTD phosphorylation states are associated with and regulate distinct stages of the transcription process.

  • The CTD and its phosphorylation couple transcription to co-transcriptional processes such as RNA processing and chromatin modification.

  • Multiple CTD modifications coalesce to regulate transcriptional processes such as transcription termination through the regulated recruitment of transcription factors.

  • The low complexity of the CTD can enable its interactions with other low-complexity protein domains and undergo liquid–liquid phase separation to form liquid-like droplets that could serve as transient membraneless compartments.

  • The high local concentration at promoters of Pol II CTDs, transcription factors and RNA from sense, divergent antisense and enhancer transcription may facilitate the formation of liquid-like droplets at promoters to regulate transcription.

Abstract

The carboxy-terminal domain (CTD) extends from the largest subunit of RNA polymerase II (Pol II) as a long, repetitive and largely unstructured polypeptide chain. Throughout the transcription process, the CTD is dynamically modified by post-translational modifications, many of which facilitate or hinder the recruitment of key regulatory factors of Pol II that collectively constitute the 'CTD code'. Recent studies have revealed how the physicochemical properties of the CTD promote phase separation in the presence of other low-complexity domains. Here, we discuss the intricacies of the CTD code and how the newly characterized physicochemical properties of the CTD expand the function of the CTD beyond the code.

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Figure 1: The composition and conservation of the CTD.
Figure 2: Transcription regulation by the CTD code.
Figure 3: Regulation of transcription termination in Saccharomyces cerevisiae by the CTD.
Figure 4: Formation of compartments by liquid–liquid phase-separation.

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Acknowledgements

The authors thank S. Buratowski, A. Mayer, C. Patil, B. Portz and F. Winston for their critical reading of the manuscript. This work was supported by US National Institutes of Health National Human Genome Research Institute (NHGRI) grants R01HG007173 (to L.S.C.) and a Burroughs Wellcome Fund Career Award at the Scientific Interface (to L.S.C.). K.M.H. was supported by a US National Science Foundation Graduate Research Fellowship (DGE1144152).

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  1. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Kevin M. Harlen & L. Stirling Churchman

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  1. Kevin M. Harlen
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Correspondence to L. Stirling Churchman.

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PowerPoint slides

Glossary

Low complexity

Protein domains with low variability of amino acids.

Multivalent interactions

Weak non-covalent interactions between biological molecules.

Liquid–liquid phase separation

The process of forming fluid, liquid-like droplets or compartments.

Promoter-proximal pausing

In metazoans, highly regulated pausing of RNA polymerase II downstream of promoters, which controls the transition into productive transcription elongation.

Bromodomain-containing protein 4

(BRD4). A transcription regulation factor that binds to acetylated chromatin and has atypical carboxy-terminal domain kinase activity.

RNA polymerase II-associated factor 1

(PAF1). A transcription elongation complex that regulates both transcription and chromatin modification.

Cryptic unstable transcripts

(CUTs). Non-coding RNAs that are rapidly degraded by the nuclear exosome.

Cajal bodies

Membrane-less nuclear compartments comprising mainly RNA and protein and where RNA processing and maturation occurs.

P bodies

Membrane-less cytoplasmic compartments where several RNA processing events occur.

Hydrogels

Macromolecular polymers composed of a network of multivalent interactions.

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Harlen, K., Churchman, L. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain. Nat Rev Mol Cell Biol 18, 263–273 (2017). https://doi.org/10.1038/nrm.2017.10

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