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Instruments / Technical Area	Publication Details	Published
I24-Microfocus Macromolecular Crystallography	Structure of human RNA polymerase III Ewan Phillip Ramsay , Guillermo Abascal-Palacios , Julia L. Daiß , Helen King , Jerome Gouge , Michael Pilsl , Fabienne Beuron , Edward Morris , Philip Gunkel , Christoph Engel , Alessandro Vannini Nature Communications 11 DOI: 10.1038/s41467-020-20262-5 Diamond Proposal Number(s): [8015, 10088] Open Access Show Abstract ▼ 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.	Dec 2020
Krios I-Titan Krios I at Diamond	Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome Sarah V. Faull , Andy M. C. Lau , Chloe Martens , Zainab Ahdash , Kjetil Hansen , Hugo Yebenes , Carla Schmidt , Fabienne Beuron , Nora B. Cronin , Edward Morris , Argyris Politis Nature Communications 10 DOI: 10.1038/s41467-019-11772-y Diamond Proposal Number(s): [15621, 16023] Open Access Show Abstract ▼ Abstract: Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members.	Sep 2019
Krios II-Titan Krios II at Diamond	Structural basis of RNA polymerase III transcription initiation Guillermo Abascal-palacios , Ewan Phillip Ramsay , Fabienne Beuron , Edward Morris , Alessandro Vannini Nature 553, 301 - 306 DOI: 10.1038/nature25441 Diamond Proposal Number(s): [15629, 16599, 166601] Show Abstract ▼ Abstract: RNA polymerase (Pol) III transcribes essential non-coding RNAs, including the entire pool of transfer RNAs, the 5S ribosomal RNA and the U6 spliceosomal RNA, and is often deregulated in cancer cells. The initiation of gene transcription by Pol III requires the activity of the transcription factor TFIIIB to form a transcriptionally active Pol III preinitiation complex (PIC). Here we present electron microscopy reconstructions of Pol III PICs at 3.4–4.0 Å and a reconstruction of unbound apo-Pol III at 3.1 Å. TFIIIB fully encircles the DNA and restructures Pol III. In particular, binding of the TFIIIB subunit Bdp1 rearranges the Pol III-specific subunits C37 and C34, thereby promoting DNA opening. The unwound DNA directly contacts both sides of the Pol III cleft. Topologically, the Pol III PIC resembles the Pol II PIC, whereas the Pol I PIC is more divergent. The structures presented unravel the molecular mechanisms underlying the first steps of Pol III transcription and also the general conserved mechanisms of gene transcription initiation.	Jan 2018

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