Dr Phil Mitchell

School of Biosciences

Lecturer

p.j.mitchell@sheffield.ac.uk
+44 114 222 2821

Full contact details

Dr Phil Mitchell
School of Biosciences
Firth Court
Western Bank
Sheffield
S10 2TN
Profile

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
Qualifications

Honours and distinctions

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

Building on the discovery and characterisation of the exosome ribonuclease complex (Mitchell et al., 1997Allmang 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.

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.

Publications

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Journal articles

All publications

Journal articles

Chapters

  • Butler JS & Mitchell P (2010) Rrp6, Rrp47 and Cofactors of the Nuclear Exosome In Jensen TH (Ed.), RNA Exosome (pp. 91-104). Springer RIS download Bibtex download
  • Mitchell P & Tollervey D (2010) Finding the Exosome In Jensen TH (Ed.), RNA Exosome (pp. 1-8). Springer RIS download Bibtex download
  • Mitchell P (2003) The role of the exosome and Ski complexes in mRNA turnover In Brakier-Gingras L & Lapointe J (Ed.), Translation Mechanisms (pp. 223-236). Springer RIS download Bibtex download
  • Brimacombe R, Mitchell P & Mueller F (1996) The organisation of rRNA, tRNA and mRNA in the ribosome In Zimmermann RA & Dahlberg AE (Ed.), Ribosomal RNA: Structure, Evolution, Processing, and Function in Protein Biosynthesis CRC Press Inc RIS download Bibtex download
  • Brimacombe R, Greuer B, Gulle H, Kosack M, Mitchell P, O∫wald M, Stade K & Stiege W (1990) New techniques for the analysis of intra-RNA and RNA-protein cross-linking data from ribosomes In Spedding G (Ed.), Ribosomes and Protein Synthesis: A Practical Approach (pp. 131-159). Oxford University Press RIS download Bibtex download
  • Wong M, Rand-Weaver M, Mitchell P & Price RG (1987) Biochemical and immunological characterisation of basement membranes in renal disease In Reid E, Cook GMW & Luzio JP (Ed.), Cells, Membranes, and Disease: Including Renal: Cells, Membranes, and Disease, Including Renal Vol 17 (pp. 465-474). Plenum Press RIS download Bibtex download

Conference proceedings papers

  • BRIMACOMBE R, DORING T, GREUER B, JUNKE N, MITCHELL P, MULLER F, OSSWALD M, RINKEAPPEL J & STADE K (1993) MAPPING THE FUNCTIONAL CENTER OF THE ESCHERICHIA-COLI RIBOSOME. TRANSLATIONAL APPARATUS (pp 433-444) RIS download Bibtex download
  • BRIMACOMBE R, GORNICKI P, GREUER B, MITCHELL P, OSSWALD M, RINKEAPPEL J, SCHULER D & STADE K (1990) THE 3-DIMENSIONAL STRUCTURE AND FUNCTION OF ESCHERICHIA-COLI RIBOSOMAL-RNA, AS STUDIED BY CROSS-LINKING TECHNIQUES. BIOCHIMICA ET BIOPHYSICA ACTA, Vol. 1050(1-3) (pp 8-13) RIS download Bibtex download

Website content

  • Mitchell P (2006) mRNA turnover. RIS download Bibtex download

Preprints

Teaching activities

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)