Mitchell, Phil, Dr

Dr Phil Mitchell

School of Biosciences

Lecturer

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

Firth Court

Full contact details

Dr Phil Mitchell
School of Biosciences
Firth Court
Western Bank
91ֱ��
S10 2TN

Profile

Career history

2004 - present: Lecturer, University of 91ֱ��
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 (; ), 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 (). 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

Show: Featured publications All publications

Featured publications

Journal articles

Schuch B, Feigenbutz M, Makino DL, Falk S, Basquin C, Mitchell P & Conti E (2014) . EMBO Journal, 33(23), 2829-2846.
Mitchell P (2014) . Biochemical Society Transactions, 42(4), 1129-1134.
Feigenbutz M, Garland W, Turner M & Mitchell PJ (2013) The exosome cofactor Rrp47 is critical for the stability and normal expression of its associated exoribonuclease Rrp6 in Saccharomyces cerevisiae. PLOS One.
Garland W, Feigenbutz M, Turner M & Mitchell P (2013) . RNA, 19(12), 1659-1668.
Feigenbutz M, Jones R, Besong TMD, Harding SE & Mitchell P (2013) . J Biol Chem, 288(22), 15959-15970.
Costello JL, Stead JA, Feigenbutz M, Jones RM & Mitchell P (2011) . J Biol Chem, 286(6), 4535-4543.
Mitchell P & Tollervey D (2011) . Adv Exp Med Biol, 702, 1-8.
Mitchell P (2010) . Biochem Soc Trans, 38(4), 1088-1092.
Butler JS & Mitchell P (2010) Rrp6, Rrp47 and Cofactors of the Nuclear Exosome. Advances in Experimental Medicine and Biology, 702, 91-104.
Stead JA, Costello JL, Livingstone MJ & Mitchell P (2007) . Nucleic Acids Res, 35(16), 5556-5567.

All publications

Journal articles

Alhajouj S, Turkolmez S, Abalkhail T, Alwan ZHO, James Gilmour D, Mitchell PJ & Hettema EH (2023) . Yeast.
Turkolmez S, Chornyi S, Alhajouj S, IJlst L, Waterham HR, Mitchell PJ, Hettema EH & van Roermund CWT (2023) . Biomolecules, 13(9).
Daniels P, Hama Soor T, Levicky Q, Hettema EH & Mitchell P (2022) . RNA.
Schuch B, Feigenbutz M, Makino DL, Falk S, Basquin C, Mitchell P & Conti E (2014) . EMBO Journal, 33(23), 2829-2846.
Mitchell P (2014) . Biochemical Society Transactions, 42(4), 1129-1134.
Feigenbutz M, Garland W, Turner M & Mitchell PJ (2013) The exosome cofactor Rrp47 is critical for the stability and normal expression of its associated exoribonuclease Rrp6 in Saccharomyces cerevisiae. PLOS One.
Garland W, Feigenbutz M, Turner M & Mitchell P (2013) . RNA, 19(12), 1659-1668.
Feigenbutz M, Jones R, Besong TMD, Harding SE & Mitchell P (2013) . J Biol Chem, 288(22), 15959-15970.
Costello JL, Stead JA, Feigenbutz M, Jones RM & Mitchell P (2011) . J Biol Chem, 286(6), 4535-4543.
Mitchell P & Tollervey D (2011) . Adv Exp Med Biol, 702, 1-8.
Butler JS & Mitchell P (2010) Rrp6, Rrp47 AND COFACTORS OF THE NUCLEAR EXOSOME. ADV EXP MED BIOL, 702, 91-104.
Mitchell P (2010) . Biochem Soc Trans, 38(4), 1088-1092.
Butler JS & Mitchell P (2010) Rrp6, Rrp47 and Cofactors of the Nuclear Exosome. Advances in Experimental Medicine and Biology, 702, 91-104.
Stead JA, Costello JL, Livingstone MJ & Mitchell P (2007) . Nucleic Acids Res, 35(16), 5556-5567.
Mitchell P, Petfalski E, Houalla R, Podtelejnikov A, Mann M & Tollervey D (2003) . Mol Cell Biol, 23(19), 6982-6992.
Mitchell P & Tollervey D (2003) . Mol Cell, 11(5), 1405-1413.
Mitchell P & Tollervey D (2001) . Curr Opin Cell Biol, 13(3), 320-325.
Mitchell P (2001) . Methods Enzymol, 342, 356-364.
Mitchell P & Tollervey D (2000) . Nat Struct Biol, 7(10), 843-846.
Allmang C, Mitchell P, Petfalski E & Tollervey D (2000) . Nucleic Acids Res, 28(8), 1684-1691.
Mitchell P & Tollervey D (2000) . Curr Opin Genet Dev, 10(2), 193-198.
Allmang C, Kufel J, Chanfreau G, Mitchell P, Petfalski E & Tollervey D (1999) . EMBO J, 18(19), 5399-5410.
Allmang C, Petfalski E, Podtelejnikov A, Mann M, Tollervey D & Mitchell P (1999) . Genes Dev, 13(16), 2148-2158.
Mitchell P, Petfalski E, Shevchenko A, Mann M & Tollervey D (1997) The exosome: A conserved eukaryotic RNA processing complex containing multiple 3'->5' exoribonucleases. CELL, 91(4), 457-466.
Mitchell P, Petfalski E & Tollervey D (1996) . Genes Dev, 10(4), 502-513.
Lygerou Z, Mitchell P, Petfalski E, Séraphin B & Tollervey D (1994) . Genes Dev, 8(12), 1423-1433.
Döring T, Mitchell P, Osswald M, Bochkariov D & Brimacombe R (1994) The decoding region of 16S RNA; a cross-linking study of the ribosomal A, P and E sites using tRNA derivatized at position 32 in the anticodon loop.. EMBO J, 13(11), 2677-2685.
Mitchell P, Stade K, Osswald M & Brimacombe R (1993) . Nucleic Acids Res, 21(4), 887-896.
Brimacombe R, Mitchell P, Osswald M, Stade K & Bochkariov D (1993) . FASEB J, 7(1), 161-167.
SMITH JE, COOPERMAN BS & MITCHELL P (1992) METHYLATION SITES IN ESCHERICHIA-COLI RIBOSOMAL-RNA - LOCALIZATION AND IDENTIFICATION OF 4 NEW SITES OF METHYLATION IN 23S RIBOSOMAL-RNA. BIOCHEMISTRY-US, 31(44), 10825-10834.
LIM V, VENCLOVAS C, SPIRIN A, BRIMACOMBE R, MITCHELL P & MULLER F (1992) HOW ARE TRANSFER-RNAS AND MESSENGER-RNA ARRANGED IN THE RIBOSOME - AN ATTEMPT TO CORRELATE THE STEREOCHEMISTRY OF THE TRANSFER-RNA MESSENGER-RNA INTERACTION WITH CONSTRAINTS IMPOSED BY THE RIBOSOMAL TOPOGRAPHY. NUCLEIC ACIDS RES, 20(11), 2627-2637.
MITCHELL P, OSSWALD M & BRIMACOMBE R (1992) IDENTIFICATION OF INTERMOLECULAR RNA CROSS-LINKS AT THE SUBUNIT INTERFACE OF THE ESCHERICHIA-COLI RIBOSOME. BIOCHEMISTRY-US, 31(11), 3004-3011.
MITCHELL P, OSSWALD M, SCHUELER D & BRIMACOMBE R (1990) SELECTIVE ISOLATION AND DETAILED ANALYSIS OF INTRA-RNA CROSS-LINKS INDUCED IN THE LARGE RIBOSOMAL-SUBUNIT OF ESCHERICHIA-COLI - A MODEL FOR THE TERTIARY STRUCTURE OF THE TRANSFER-RNA BINDING DOMAIN IN 23S-RNA. NUCLEIC ACIDS RES, 18(15), 4325-4333.

Chapters

Butler JS & Mitchell P (2010) Rrp6, Rrp47 and Cofactors of the Nuclear Exosome In Jensen TH (Ed.), RNA Exosome (pp. 91-104). Springer
Mitchell P & Tollervey D (2010) Finding the Exosome In Jensen TH (Ed.), RNA Exosome (pp. 1-8). Springer
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
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
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
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

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)
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)

Website content

Mitchell P (2006) mRNA turnover.

Preprints

Alhajouj S, Turkolmez S, Abalkhail T, Alwan ZHO, Gilmour DJ, Mitchell PJ & Hettema EH (2023) , Cold Spring Harbor Laboratory.

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)