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Mol Cell. 2019 Apr 4;74(1):158-172.e9. doi: 10.1016/j.molcel.2019.01.027. Epub 2019 Feb 25.

Selective Roles of Vertebrate PCF11 in Premature and Full-Length Transcript Termination.

Author information

1
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: kinga.kamieniarz-gdula@path.ox.ac.uk.
2
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
3
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria.
4
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
5
Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
6
Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria. Electronic address: andrea.pauli@imp.ac.at.
7
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: nicholas.proudfoot@path.ox.ac.uk.

Abstract

The pervasive nature of RNA polymerase II (Pol II) transcription requires efficient termination. A key player in this process is the cleavage and polyadenylation (CPA) factor PCF11, which directly binds to the Pol II C-terminal domain and dismantles elongating Pol II from DNA in vitro. We demonstrate that PCF11-mediated termination is essential for vertebrate development. A range of genomic analyses, including mNET-seq, 3' mRNA-seq, chromatin RNA-seq, and ChIP-seq, reveals that PCF11 enhances transcription termination and stimulates early polyadenylation genome-wide. PCF11 binds preferentially between closely spaced genes, where it prevents transcriptional interference and consequent gene downregulation. Notably, PCF11 is sub-stoichiometric to the CPA complex. Low levels of PCF11 are maintained by an auto-regulatory mechanism involving premature termination of its own transcript and are important for normal development. Both in human cell culture and during zebrafish development, PCF11 selectively attenuates the expression of other transcriptional regulators by premature CPA and termination.

KEYWORDS:

PCF11; RNA 3′ processing; alternative polyadenylation; attenuation; autoregulation; human; premature termination; regulation of gene expression; transcription termination; zebrafish

PMID:
30819644
PMCID:
PMC6458999
DOI:
10.1016/j.molcel.2019.01.027
[Indexed for MEDLINE]
Free PMC Article

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