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PHF3 regulates neuronal gene expression through the new Pol II CTD reader domain SPOC

Lisa-Marie Appel, View ORCID ProfileVedran Franke, Melania Bruno, Irina Grishkovskaya, Aiste Kasiliauskaite, Ursula E. Schoeberl, Martin G. Puchinger, Sebastian Kostrhon, Etienne Beltzung, View ORCID ProfileKarl Mechtler, Gen Lin, Anna Vlasova, Martin Leeb, Rushad Pavri, Alexander Stark, Altuna Akalin, Richard Stefl, Carrie Bernecky, Kristina Djinovic-Carugo, Dea Slade
doi: https://doi.org/10.1101/2020.02.11.943159
Lisa-Marie Appel
1Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Vedran Franke
2The Berlin Institute for Medical Systems Biology, Max Delbrück Center, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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  • ORCID record for Vedran Franke
Melania Bruno
1Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Irina Grishkovskaya
3Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, 1030 Vienna, Austria
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Aiste Kasiliauskaite
4CEITEC-Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic
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Ursula E. Schoeberl
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna Biocenter (VBC), 1030 Vienna, Austria
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Martin G. Puchinger
3Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, 1030 Vienna, Austria
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Sebastian Kostrhon
1Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Etienne Beltzung
1Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Karl Mechtler
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna Biocenter (VBC), 1030 Vienna, Austria
6Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, Austria
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Gen Lin
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna Biocenter (VBC), 1030 Vienna, Austria
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Anna Vlasova
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna Biocenter (VBC), 1030 Vienna, Austria
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Martin Leeb
7Department of Microbiology, Immunobiology and Genetics, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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Rushad Pavri
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna Biocenter (VBC), 1030 Vienna, Austria
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Alexander Stark
5Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, Vienna Biocenter (VBC), 1030 Vienna, Austria
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Altuna Akalin
2The Berlin Institute for Medical Systems Biology, Max Delbrück Center, Robert-Rössle-Straße 10, 13125 Berlin, Germany
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Richard Stefl
4CEITEC-Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic
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Carrie Bernecky
8Institute of Science and Technology Austria (IST Austria), Am Campus 1, 3400 Klosterneuburg, Austria
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Kristina Djinovic-Carugo
3Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Campus Vienna Biocenter 5, 1030 Vienna, Austria
9Department of Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
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Dea Slade
1Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna Biocenter (VBC), Dr. Bohr-Gasse 9, 1030 Vienna, Austria
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  • For correspondence: dea.slade@univie.ac.at
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SUMMARY

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a new CTD-binding factor that negatively regulates transcription and mRNA stability. The PHF3 SPOC domain preferentially binds to CTD repeats phosphorylated on Serine-2 and PHF3 tracks with Pol II across the length of genes. PHF3 competes with TFIIS for Pol II binding through its TFIIS-like domain (TLD), thus inhibiting TFIIS-mediated rescue of backtracked Pol II. PHF3 knock-out or PHF3 SPOC deletion in human cells result in gene upregulation and a global increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 is a prominent effector of neuronal gene regulation at the interface of transcription elongation and mRNA decay.

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Posted February 12, 2020.
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PHF3 regulates neuronal gene expression through the new Pol II CTD reader domain SPOC
Lisa-Marie Appel, Vedran Franke, Melania Bruno, Irina Grishkovskaya, Aiste Kasiliauskaite, Ursula E. Schoeberl, Martin G. Puchinger, Sebastian Kostrhon, Etienne Beltzung, Karl Mechtler, Gen Lin, Anna Vlasova, Martin Leeb, Rushad Pavri, Alexander Stark, Altuna Akalin, Richard Stefl, Carrie Bernecky, Kristina Djinovic-Carugo, Dea Slade
bioRxiv 2020.02.11.943159; doi: https://doi.org/10.1101/2020.02.11.943159
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PHF3 regulates neuronal gene expression through the new Pol II CTD reader domain SPOC
Lisa-Marie Appel, Vedran Franke, Melania Bruno, Irina Grishkovskaya, Aiste Kasiliauskaite, Ursula E. Schoeberl, Martin G. Puchinger, Sebastian Kostrhon, Etienne Beltzung, Karl Mechtler, Gen Lin, Anna Vlasova, Martin Leeb, Rushad Pavri, Alexander Stark, Altuna Akalin, Richard Stefl, Carrie Bernecky, Kristina Djinovic-Carugo, Dea Slade
bioRxiv 2020.02.11.943159; doi: https://doi.org/10.1101/2020.02.11.943159

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