Professor Jon R Sayers, FRSB
Professor of Functional Genomics
Deputy Head of Department
Department of Infection, Immunity & Cardiovascular Disease
Henry Wellcome Laboratories for Medical Research
University of Sheffield
Beech Hill Rd
Sheffield S10 2RX
I teach graduate classes in biochemistry, protein/DNA sequence analysis, protein engineering of novel therapeutics and biotechnology. I studied Chemistry at the University of Birmingham, obtaining my B.Sc. in 1983 where I went on to gain a Ph.D. (1986) in the Nucleic Acids Groups directed by Prof. Stan Jones and Prof. Dick Walker. Thesis title; Synthesis of Nucleoside Analogues. In 1986 I joined the Max-Planck-Institut for Experimental Medicine, Gottingen, Germany under Prof. Fritz Eckstein as a postdoctoral researcher where I studied restriction endonuclease-DNA interactions and helped develop a widely used system for site-directed mutagenesis (the 'phosphorothioate approach'). I also became interested in flap endonucleases, or 5'-3' exonucleases. In 1991 I moved to a Lectureship in the Biochemistry Department at the University of Wales, Bangor, UK, where I established a research group working on various aspects of molecular recognition. Projects included work on novel phage T5 proteins, a schistosomal protease (in collaboration with Dr. Mike Doenhoff), genetic variability of Haemophilus influenzae (in collaboration with Dr. Tony Howard, PHLS Cardiff), generation of new binding proteins and flap endonucleases. I moved to Sheffield in 1995, was promoted to Senior Lecturer in 1997, to a Readership in 1999 and a personal chair in 2006. I have developed an interest in proteins secreted by Gram negative bacterial pathogens and how they interact with the host. We use a wide range of molecular and cell biological and biophysical techniques to unravel the detail of such interactions aided by close collaboration with structural biologists in Sheffield and the United States. I was elected as a Fellow of the Royal Society of Biology in 2013.
In 2001 I become a director and co-founder of Asterion Ltd., a biotech spin-off company (see Asterion Ltd.)
I have written an article for "The Biochemist" describing the trials and tribulations of an academic involved in the setting up of a spin-out company. It can be found under 'downloads'.
The group is involved in four main areas:
- Molecular mechanisms involved in protein:DNA interactions.
- Microbial proteases, pathogenesis and the host response.
- Novel applications of biotechnology to biomedical research and drug development.
- Structure-based drug design.
Ongoing topics include the following:
A novel helical arch discovered in a 5'-3' exonuclease could explain how this class of essential replicative enzymes digest their nucleic acids substrates. See Ceska, Sayers, Stier & Suck (1996) Nature, 382, 90-93.
These enzymes are involved in replication of the lagging strand during DNA synthesis and in repair of DNA damage. Some members possess structure-specific endonuclease activity as well as exonuclease and RNase H activities. We have shown that a member of this important class of enzymes contains a novel DNA-binding motif, the helical arch (see above picture of the T5 exonuclease). We are using site-directed mutagenesis, crystallography and kinetic studies to determine how these complicated enzymes function. We have cloned and expressed a number of exonucleases from bacteria including the human pathogen Haemophilus influenzae. In collaboration with Dr. Dietrich Suck and Dr. Tom Ceska at the EMBL (Heidelberg) a structural model is emerging for this interesting group of enzymes. This work is funded by the BBSRC, The Wellcome Trust and the White Roses Consortium.
Many important biological processes such as gene expression are regulated by proteins binding to specific DNA sequences. We are studying novel DNA-binding proteins from viruses and pathogenic bacteria. We have chosen proteins with no sequence homologues in the databases. Such proteins are thus unique and studying how they recognize their target sequences should provide new insights into molecular recognition processes. This work is funded by the Bardhan Trust for Educational Research.
We have discovered a strong link between carriage of gene containing a highly variable domain and pathogenesis in these two meningitis-causing organisms. Collaborative work is underway with Dr. Tony Howard (PHLS, Bangor) and Professor Robert Read (Infection & Immunity, Sheffield). We have recently reported data demonstrating that pathogenic strains of Neisseria meningitidis produce higher levels of an enzyme capable of destroying human antibodies. The protease attacks IgA1, a major component of the mucosal immune system. This work has been funded by The Meningitis Research Foundation and the Colin Beattie Memorial Fund and is currently supported by the Medical Research Council.
I teach graduate-level biochemistry, molecular & structural biology, bioinformatics and biotechnology in relation to biomedical research and drug discovery.
- Honorary Treasurer and Trustee of the Biochemical Society, 2008-2012.
- Director of Portland Press, 2008-2012.
- Editorial board member of The Biochemical Journal, 2007 - present
- Ross R, Artymiuk P, Sayers J. Growth hormone fusion proteins. 2013, Granted US Patent No. 8,470,559.
(PLEASE NOTE although this has the same title and author as patent no. 8,293,709 which was already included, it is a separate patent granted in 2013).
- Ross R, Artymiuk P, Sayers J. Growth hormone fusion proteins. 2012, Granted US Patent No. 8,293,709.
- Artymiuk, P, Ross R, Sayers J. Modified growth hormone polypeptides 2012, Granted US Patent No. 8,273,552.
- Ross R, Artymiuk P, Sayers J. Fusion protein comprising growth hormone and growth hormone receptor. 2012 Granted US Patent No. 8,173,782.
- Ross R, Sayers J, Artymiuk P. Modified growth hormone fusion polypeptides, 2009, Granted US Patent No. 7524649.
- Ross R, Sayers J, Artymiuk P. Cytokine polypeptides and antibodies containing a signal sequence for the attachment of glycosylphosphatidylinositol, 2009, Granted US Patent No. 7625998.
- Ross R, Artymiuk P, Sayers J. Fusion protein comprising growth hormone and growth hormone receptor. 2008 Granted US Patent No. 7,446,183.
- Duff, G.W., Sayers, J.R., Vitovski, S. Designer proteases. 2002 Granted US Patent No.6,383,775.
For Key Publications see below. For a full list of publications click here.
- Wong IN, Sayers JR & Sanders CM (2016) Bacteriophage T5 gene D10 encodes a branch-migration protein. Scientific Reports, 6. View this article in WRRO
- Wilkinson IR, Pradhananga SL, Speak R, Artymiuk PJ, Sayers JR & Ross RJ (2016) A long-acting GH receptor antagonist through fusion to GH binding protein.. Sci Rep, 6, 35072-35072. View this article in WRRO
- AlMalki FA, Flemming CS, Zhang J, Feng M, Sedelnikova SE, Ceska T, Rafferty JB, Sayers JR & Artymiuk PA (2016) Direct observation of DNA threading in flap endonuclease complexes. Nature Structural and Molecular Biology, 23, 640-646. View this article in WRRO
- Anstey-Gilbert CS, Hemsworth GR, Flemming CS, Hodskinson MRG, Zhang J, Sedelnikova SE, Stillman TJ, Sayers JR & Artymiuk PJ (2013) The structure of Escherichia coli ExoIX—implications for DNA binding and catalysis in flap endonucleases. Nucleic Acids Research. View this article in WRRO
- Tomlinson CG, Syson K, Sengerová B, Atack JM, Sayers JR, Swanson L, Tainer JA, Williams NH & Grasby JA (2011) Neutralizing mutations of carboxylates that bind metal 2 in T5 flap endonuclease result in an enzyme that still requires two metal ions.. J Biol Chem, 286(35), 30878-30887.
- Ferrandis E, Pradhananga SL, Touvay C, Kinoshita C, Wilkinson IR, Stafford K, Wu Z, Strasburger CJ, Sayers JR, Artymiuk PJ & Ross RJ (2010) Immunogenicity, toxicology, pharmacokinetics and pharmacodynamics of growth hormone ligand-receptor fusions.. Clin Sci (Lond), 119(11), 483-491.
- Allen LM, Hodskinson MRG & Sayers JR (2009) Active site substitutions delineate distinct classes of eubacterial flap endonuclease.. Biochem J, 418(2), 285-292. View this article in WRRO
- Vitovski S, Phillips JS, Sayers J & Croucher PI (2007) Investigating the interaction between osteoprotegerin and receptor activator of NF-kappaB or tumor necrosis factor-related apoptosis-inducing ligand: evidence for a pivotal role for osteoprotegerin in regulating two distinct pathways.. J Biol Chem, 282(43), 31601-31609.
- Wilkinson IR, Ferrandis E, Artymiuk PJ, Teillot M, Soulard C, Touvay C, Pradhananga SL, Justice S, Wu Z, Leung KC, Strasburger CJ, Sayers JR & Ross RJ (2007) A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist.. Nat Med, 13(9), 1108-1113.
- Hodskinson MRG, Allen LM, Thomson DP & Sayers JR (2007) Molecular interactions of Escherichia coli ExoIX and identification of its associated 3'-5' exonuclease activity.. Nucleic Acids Res, 35(12), 4094-4102. View this article in WRRO
- Smith P, Fallon RE, Mangan NE, Walsh CM, Saraiva M, Sayers JR, McKenzie ANJ, Alcami A & Fallon PG (2005) Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity. J EXP MED, 202(10), 1319-1325. View this article in WRRO
- Feng M, Patel D, Dervan JJ, Ceska T, Suck D, Haq I & Sayers JR (2004) Roles of divalent metal ions in flap endonuclease-substrate interactions.. Nat Struct Mol Biol, 11(5), 450-456.
- Tock MR, Frary E, Sayers JR & Grasby JA (2003) Dynamic evidence for metal ion catalysis in the reaction mediated by a flap endonuclease.. EMBO J, 22(5), 995-1004.
- Dervan JJ, Feng M, Patel D, Grasby JA, Artymiuk PJ, Ceska TA & Sayers JR (2002) Interactions of mutant and wild-type flap endonucleases with oligonucleotide substrates suggest an alternative model of DNA binding.. Proc Natl Acad Sci U S A, 99(13), 8542-8547.
- Vitovski S, Dunkin KT, Howard AJ & Sayers JR (2002) Nontypeable Haemophilus influenzae in carriage and disease: a difference in IgA1 protease activity levels.. JAMA, 287(13), 1699-1705.
- Garforth SJ, Ceska TA, Suck D & Sayers JR (1999) Mutagenesis of conserved lysine residues in bacteriophage T5 5'-3' exonuclease suggests separate mechanisms of endo-and exonucleolytic cleavage.. Proc Natl Acad Sci U S A, 96(1), 38-43.
- Smith MCM, Burns N, Sayers JR, Sorrell JA, Casjens SR & Hendrix RW (1998) Bacteriophage collagen. SCIENCE, 279(5358), 1834-1834.
- Ceska TA, Sayers JR, Stier G & Suck D (1996) A helical arch allowing single-stranded DNA to thread through T5 5'-exonuclease. NATURE, 382(6586), 90-93.