RNA Processing and Quality Control
David Tollervey studied for a BSc in Microbiology in Edinburgh and then for a PhD in Genetics at Cambridge in the lab of Herb Arst. He then moved to the University of California, San Francisco, as a postdoctoral fellow in the laboratory of Christine Guthrie. In 1983 he relocated to a permanent post at the Institut Pasteur in Paris, which he left in 1988 to move to the European Molecular Biology Laboratory (EMBL) in Heidelberg as a group leader. He returned to Edinburgh in 1997 as Professor of RNA Biology and a Wellcome Trust Principal Research Fellow.
From 2011 to 2021 he has served as Director of the Wellcome Centre for Cell Biology. He is a Fellow of the Royal Society, and of the Royal Society of Edinburgh, a member of EMBO and Past President of the international RNA Society.
The aim of the Tollervey group is to understand the nuclear pathways that process newly transcribed RNAs and assemble RNA-protein complexes, the mechanisms that regulate these pathways and the surveillance activities that monitor their fidelity. His current research combines in vivo UV crosslinking and high-throughput sequencing to precisely identify sites of RNA-protein interaction and RNA-RNA basepairing, with genetics, biochemistry, transcriptomics and bioinformatics.
With the arrival of the COVID-19 pandemic, we have commenced work on SARS-CoV-2
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Katie Bexley, Stefan Bresson, Aziz El Hage, Aleksandra Helwak, Alexandra Lehmann, Laura Milligan, Elisabeth Petfalski, Michaela Ristová, Nic Robertson, Thomas Tan and Pin Tong
RNA Processing and Quality Control
RNA-protein interactions have important functions at all steps in gene expression, including transcription, RNA processing and mRNA translation. RNA defects underpin many genetic diseases, while responses to environmental stress are frequently mediated by altered RNA-protein interactions. Over the past year we have made good progress in understanding stress responses in yeast and have started to apply these insights in human cells. We have also applied our techniques to understand the molecular basis of RNA-linked disease, and this report will focus on these advances.
Coronavirus infection involves a complex pathway of coding and non-coding RNA synthesis. To better understand the biology of viral gene expression and replication we generated constructs for studying RNA interactions by viral proteins (doi: 10.12688/wellcomeopenres.16322.1). We are also following host and viral RNA metabolism and RNA-protein interactions over detailed time courses during infection (Fig. 1). This is giving insights into the timing and regulation of viral RNA replication and virus-host interactions.
In the 1980s, we discovered that eukaryotic cells contain large numbers of small nucleolar RNAs (snoRNAs). More recently, we applied CLASH, a proximity ligation technique developed in the group, to systematically map snoRNA interactions with rRNAs and mRNAs in yeast and human cells (10.12688/wellcomeopenres.14735.2; bioRxiv 2021.07.22.451324). We are now characterising the basis of the neurological disease Prader-Willi Syndrome, which can be caused by loss of a single family of brain-enriched snoRNAs called SNORD116. We have created a PWS model system based on pre-neuronal cells that lack SNORD116, and are determining the role of this snoRNA in neuronal differentiation. From our preliminary data, we already know that lack of SNORD116 expression leads to substantial alterations in gene expression and accelerates the differentiation process. Now we aim to determine the molecular mechanisms.
We recently identified the molecular defects underlying another genetic disease Cartilage Hair Dysplasia (CHD), characterised by reduced stature and immunodeficiency. This can be caused by mutations in RMRP, another nucleolar ncRNA. RMRP provides the core of an RNA-protein complex with RNA cleavage activity, RNase MRP, which we characterized in the 1990s. Mutations in the mouse RMRP gene impaired T cell activation, which must occur during immune response, and delayed pre-ribosomal RNA (pre-rRNA) processing. Recapitulation of the major disease-linked mutation in human cells (Robertson et al. 2022) induced a defect in pre-rRNA processing, leading to reduced accumulation of the large ribosomal subunit (Fig. 2). A similar pre-rRNA processing defect was seen in patient-derived fibroblasts, establishing CHD as a disease of ribosome synthesis or “ribosomopathy”.
Together, these analyses increased our understanding of important, disease-related pathways in RNA biology.
Figure 1. Analyses of the Coronavirus infection time-course
Figure 2. Recapitulation of disease-linked mutations in the human lncRNA, RMRP
Robertson, N., Shchepachev, V., Wright, D., Turowski, T.W., Spanos, C., Helwak, A., Zamoyska, R., and Tollervey, D. (2022). A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis. Nat Commun 13, 649.
Bresson, S., Shchepachev, V., Spanos, C., Turowski, T., Rappsilber, J., and Tollervey, D. (2020). Stress-induced translation inhibition through rapid displacement of scanning initiation factors. Mol Cell 80, 470-484.
Turowski, T.W., Petfalski, E., Goddard, B.D., French, S.L., Helwak, A., and Tollervey, D. (2020). Nascent Transcript Folding Plays a Major Role in Determining RNA Polymerase Elongation Rates. Mol Cell 79, 488-503.e411.