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Dr Phil Mitchell

Lecturer


Tel: 0114 222 2821
Email: p.j.mitchell@sheffield.ac.uk

Research

Research Precis

fig1Building on the discovery and characterisation of the exosome ribonuclease complex (Mitchell et al., 1997; Allmang et al., 1999), my lab’s research addresses the molecular mechanisms of RNA quality control in eukaryotic cells.

Counter-intuitively, much of the RNA that a eukaryotic cell produces is rapidly degraded after being transcribed. This widespread turnover reflects highly active RNA quality control systems and the widespread transcription and degradation of unstable noncoding RNAs, as well as the processing of functional RNA from much longer precursors. Key to many of these processes is the exosome ribonuclease (RNase) complex. Mutations within genes of the exosome directly underlie forms of neurodegenerative disease and autoimmunity and are also associated with multiple myeloma. We are interested in understanding how RNases recognise their substrates, how the activities of these enzymes are regulated, and how they impact on human health and disease. We use a range of complementary experimental techniques, including cellular RNA analyses, molecular genetics, protein biochemistry, cell imaging and in vitro RNA degradation assays. Our current research aims include determining the importance of the different substrate pathways that exist through the exosome complex, understanding the functional redundancy between the exosome and Rex1 RNases, and defining the molecular interactions that are mediated through eukaryotic proteins containing the C1D domain, which is exemplified by the exosome subunit Rrp47.

Research Keywords

RNA, gene expression, ribonuclease, exosome, quality control

Examples of currently active research projects are given below. Prospective home and international PhD students can apply for a PhD position in our lab here.

For further information, contact p.j.mitchell@sheffield.ac.uk.



Addressing the functional significance of distinct paths to catalytic sites within the exosome

The exosome RNase complex contains two associated catalytic subunits, one of which has two distinct catalytic sites (Mitchell, 2014). Substrates can be targeted to these enzymes along a number of multiple pathways. Which RNA substrates utilise which pathway? Is there an obligatory or stochastic choice of pathway for a given RNA? Is the flux through a given pathway subject to regulation through growth conditions?

Analysis of the exoribonuclease Rex1

Inhibition of one exosome catalytic subunit renders cells dependent upon another RNase called Rex1. What are the RNA processing or degradation pathways that require either the exosome or Rex1 activity, and which of those are essential for cell growth? What specific features of Rex1 allow it to substitute for the exosome?

Optimisation of gene expression routes for heterologous protein expression in CHO cells

CHO cells are commonly used as a vehicle for the production of heterologous proteins in the biopharmaceutical industry. We are currently using gene knock down and knock in approaches to increase the expression level of target recombinant proteins for potential use in industrial scale applications.

Teaching

Level 4 Modules

MBB405 Advanced Research Topics (Module Coordinator)

Level 3 Modules

MBB325 The RNA World
MBB362 Biochemistry Data Handling

Level 2 Modules

MBB267 Genes, Genomes and Chromosomes (Module Coordinator)

Level 1 Modules

MBB164 Molecular Biology (Module Coordinator)

Career History

Career History

  • 2004 - present: Lecturer, University of Sheffield
  • 1997 - 2004: PDRA (Tollervey lab), Wellcome Trust Centre for Cell Biology, University of Edinburgh
  • 1993 - 1996: Research Fellow (Tollervey lab), EMBL, Heidelberg, Germany
  • 1993: Visiting Scientist (Zimmerman lab), University of Amherst, USA
  • 1991 - 1992: PDRA (Brimacombe lab), Max Planck Institute for Molecular Genetics, Berlin, Germany
  • 1988 - 1990: PhD, King’s College, University of London

Honours and Distinctions

  • 2011 - present: Associate Editor, International Journal of Biochemistry and Molecular Biology
  • 1993 - 1996: EMBO Research fellowship








































Selected Publications

Journal articles