2. Academic Validation
  3. Structure of human RNA polymerase III

Structure of human RNA polymerase III

  • Nat Commun. 2020 Dec 17;11(1):6409. doi: 10.1038/s41467-020-20262-5.
Ewan Phillip Ramsay 1,  Guillermo Abascal-Palacios 1,  Julia L Daiß 2,  Helen King 1,  Jerome Gouge 1,  Michael Pilsl 2,  Fabienne Beuron 1,  Edward Morris 1,  Philip Gunkel 3,  Christoph Engel 4,  Alessandro Vannini 5 6
Affiliations

Affiliations

  • 1 Division of Structural Biology, The Institute of Cancer Research, London, SW7 3RP, UK.
  • 2 Regensburg Center for Biochemistry, University of Regensburg, 93053, Regensburg, Germany.
  • 3 Max Planck Institute for Biophysical Chemistry, Research Group Nuclear Architecture, 37077, Göttingen, Germany.
  • 4 Regensburg Center for Biochemistry, University of Regensburg, 93053, Regensburg, Germany. christoph.engel@ur.de.
  • 5 Division of Structural Biology, The Institute of Cancer Research, London, SW7 3RP, UK. alessandro.vannini@fht.org.
  • 6 Fondazione Human Technopole, Structural Biology Research Centre, 20157, Milan, Italy. alessandro.vannini@fht.org.
PMID: 33335104 DOI: 10.1038/s41467-020-20262-5
Abstract

In eukaryotes, RNA Polymerase (Pol) III is specialized for the transcription of tRNAs and Other short, untranslated RNAs. Pol III is a determinant of cellular growth and lifespan across eukaryotes. Upregulation of Pol III transcription is observed in Cancer and causative Pol III mutations have been described in neurodevelopmental disorders and hypersensitivity to viral Infection. Here, we report a cryo-EM reconstruction at 4.0 Å of human Pol III, allowing mapping and rationalization of reported genetic mutations. Mutations causing neurodevelopmental defects cluster in hotspots affecting Pol III stability and/or biogenesis, whereas mutations affecting viral sensing are located in proximity to DNA binding regions, suggesting an impairment of Pol III cytosolic viral DNA-sensing. Integrating x-ray crystallography and SAXS, we also describe the structure of the higher eukaryote specific RPC5 C-terminal extension. Surprisingly, experiments in living cells highlight a role for this module in the assembly and stability of human Pol III.

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