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Mol Cell. 2019 Jun 20;74(6):1164-1174.e4. doi: 10.1016/j.molcel.2019.04.008. Epub 2019 May 1.

Crosstalk between RNA Pol II C-Terminal Domain Acetylation and Phosphorylation via RPRD Proteins.

Author information

1
J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
2
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Donnelly Centre, University of Toronto, Toronto, ON, Canada.
4
J. David Gladstone Institutes, San Francisco, CA 94158, USA.
5
Structural Genomics Consortium, University of Toronto, ON, Canada.
6
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences (QBC), University of California, San Francisco, San Francisco, CA 94143, USA.
7
J. David Gladstone Institutes, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences (QBC), University of California, San Francisco, San Francisco, CA 94143, USA.
8
J. David Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: melanie.ott@gladstone.ucsf.edu.

Abstract

Post-translational modifications of the RNA polymerase II C-terminal domain (CTD) coordinate the transcription cycle. Crosstalk between different modifications is poorly understood. Here, we show how acetylation of lysine residues at position 7 of characteristic heptad repeats (K7ac)-only found in higher eukaryotes-regulates phosphorylation of serines at position 5 (S5p), a conserved mark of polymerases initiating transcription. We identified the regulator of pre-mRNA-domain-containing (RPRD) proteins as reader proteins of K7ac. K7ac enhanced CTD peptide binding to the CTD-interacting domain (CID) of RPRD1A and RPRD1B proteins in isothermal calorimetry and molecular modeling experiments. Deacetylase inhibitors increased K7ac- and decreased S5-phosphorylated polymerases, consistent with acetylation-dependent S5 dephosphorylation by an RPRD-associated S5 phosphatase. Consistent with this model, RPRD1B knockdown increased S5p but enhanced K7ac, indicating that RPRD proteins recruit K7 deacetylases, including HDAC1. We also report autoregulatory crosstalk between K7ac and S5p via RPRD proteins and their interactions with acetyl- and phospho-eraser proteins.

KEYWORDS:

C-terminal domain; Pol II CTD; RNA polymerase II; acetylation; crosstalk; gene regulation; histone deacetylase; phosphorylation; post-translational modification; transcription

PMID:
31054975
PMCID:
PMC6588463
[Available on 2020-06-20]
DOI:
10.1016/j.molcel.2019.04.008

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