JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes
- National Jewish Health, United States
- School of Medicine, Univeristy of Colorado at Anschutz Medical Center, United States
- Xiamen Univeristy, China
- Children Hospital, United States
- China Agriculture University, China
- Duke University Medical Center, United States
- Max-Planck-Society, Germany
- School of Medicine, University of Pennsylvannia, United States
- Howard Hughes Medical Institute, National Jewish Health, United States
- University of California, Berkeley, United States
- Xiamen University, China
- School of Medicine, University of Colorado at Anschutz Medical Center, United States
Abstract
More than 30% of genes in higher eukaryotes are regulated by promoter-proximal pausing of RNA polymerase II (Pol II). Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. The exact mechanism on how the sequestered P-TEFb is released from the 7SK snRNP complex and recruited to Pol II CTD remains unknown. In this report, we utilize mouse and human models to reveal methylphosphate capping enzyme (MePCE), a core component of the 7SK snRNP complex, as the cognate substrate for Jumonji domain-containing 6 (JMJD6)’s novel proteolytic function. Our evidences consist of a crystal structure of JMJD6 bound to methyl-arginine, enzymatic assays of JMJD6 cleaving MePCE in vivo and in vitro, binding assays, and downstream effects of Jmjd6 knockout and overexpression on Pol II CTD phosphorylation. We propose that JMJD6 assists bromodomain containing 4 (BRD4) to recruit P-TEFb to Pol II CTD by disrupting the 7SK snRNP complex.
Data availability
Diffraction data have been deposited in PDB under the accession code 6mev,All data generated or analysed during this study are included in the manuscript and supporting files.
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Structure of JMJD6 bound to Mono-Methyl Arginine.Protein Data Bank, 6MEV.
Article and author information
Author details
Kathrin Maria Bernt
Funding
National Cancer Institute (CA201230)
- Kathrin Maria Bernt
National Institute of Allergy and Infectious Diseases (AI007405)
- Schuyler Lee
National Institute of Allergy and Infectious Diseases (AI074491)
- Haolin Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Zhiguo Zhang, Columbia University, United States
Version history
- Received: November 25, 2019
- Accepted: February 11, 2020
- Accepted Manuscript published: February 12, 2020 (version 1)
- Version of Record published: March 10, 2020 (version 2)
Copyright
© 2020, Lee et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes
eLife 9:e53930.
https://doi.org/10.7554/eLife.53930
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