Yeast Genetics Laboratory
Head of Laboratory
Gary Jones, BSc, PhD (Liverpool)
In 1982 the term prion was first coined by Stanley Prusiner to describe the nature of the scrapie infective agent. A prion is an infectious protein. It is a transmissible amyloid form of a cellular protein that replicates by converting the native protein into the same abnormal prion form. Prion and amyloid diseases of humans include Creutzfeld Jacob disease, Alzheimer's disease, Huntington disease and Type II diabetes. Much research has focused on understanding the mechanisms by which prions and amyloid arise and are maintained within an organism. In 1994 Reed Wickner proposed that the genetic behaviour of the Saccharomyces cerevisiae non-mendelian elements [ PSI + ] and [ URE3 ] could be explained if they were prions of the Sup35 and Ure2 proteins respectively. Since then much evidence has accumulated to support this proposal. The fact that prions exist in yeast provides an ideal environment for detailed genetic analysis of factors affecting prion propagation and maintenance.
Sup35p is a S. cerevisiae protein involved in termination of translation. In a state referred to as [ PSI + ], a significant portion of the Sup35 protein in the cell coalesces into nonfunctional, self-propagating, amyloid-like polymers. Thus, yeast strains that are [ PSI + ] show increased levels of nonsense suppression. We can monitor the presence of the prion in our yeast strains by a simple colour assay (figure 1). Once present, [ PSI + ] propagates by recruitment of the soluble form of Sup35p into the aggregate in a manner analogous to that of mammalian prions. A search for genetic factors affecting propagation and maintenance of [ PSI + ] has identified an essential role for molecular chaperones, namely Hsp70 and Hsp104. We have recently shown the importance of the Hsp70 ATPase domain in prion propagation and emphasised how the regulation of the Hsp70 ATPase cycle is essential for efficient prion propagation.
Our research aims at deciphering the complex relationship that exists between protein chaperones and prion/amyloid maintenance in yeast. The fact that chaperone complexes are extremely well conserved from yeast to higher eukaryotes means that our findings may be directly relevant to our understanding of prion and amyloid diseases in humans.
Figure 1- Monitoring the [PSI+] prion by a simple colour assay. The presence of the prion allows translation readthrough of an aberrant stop codon in the ADE2 gene. The consequence of this is the prion containing cells are white and cells lacking prions are red.
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Funding for our work has been supported by Science Foundation Ireland, Health Research Board, Irish Research Council for Science and Engineering Technology, Marie Curie Actions (FP6) and departmental funds.
- Marc Blondel (Brest School of Medicine, France)- Mode of action of how drugs cure prions
- Mario Fares (Trinity College Dublin, Ireland)- Evolution of molecular chaperones
- Sarah Perrett (Chinese Academy of Sciences, Beijing)- Role of Hsp70 chaperone machinery in prion propagation
- Prof. Sean Doyle (NUIM)- new therapeutics for fungal diseases
- Dr. David Fitzpatrick (NUIM)- prions in fungi and fungal evolution
- Prof. Steve Kron and Dr. Andy Truman (University of Chicago)- role of post-translational modification in modulating Hsp70 function
- Prof. Youtao Song (Liaoning University, Shenyang)- chaperone effects on yeast prion propagation
Peer Reviewed Publications
- Moran .C, G. K. Kinsella, Z. R. Zhang, S. Perrett, G. W. Jones (2013\) Mutational Analysis of Sse1 (Hsp110) Suggests an Integral Role for this Chaperone in Yeast Prion Propagation In Vivo. G3; Genes|Genomes|Genetics (Bethesda). Jun 24. doi:pii: g3.113.007112v1.
- Xu, L. Q, A. K. Buell, S. Wu, S. I. A. Cohen, L. J. Chen, S. A. Cusack, L. S. Itzhaki, H. Zhang, T. P. J. Knowles, C. M. Dobson, M. E. Welland, G. W. Jones and S. Perrett. (2013) Influence of specific Hsp70 domains on fibril formation of the yeast prion protein Ure2. Philosophical Transactions of the Royal Society Series B. Mar 25;368(1617):20110410.
- Xu L, N. Hasin, M. Shen, J. He, Y. Wang, S. Perrett, Y. Song and G. W. Jones (2013) Using steered molecular dynamics to predict and assess Hsp70 substrate- binding domain mutants that alter prion propagation. PLOS Computational Biology. 2013;9(1):e1002896.
- Fares M. A, O. Keane, L. Carretero-Paulet, C. Toft and G. W. Jones (2013) The roles of whole genome and small-scale duplications in the functional specialization of Saccharomyces cerevisiae genes. PLOS Genetics 9(1): e1003176.
- Truman A. W, K. Kristjansdottir, D. Wolfgeher, N. Hasin, S. Polier, H. Zhang, S. Perrett, C. Prodromou, G. W. Jones and S. J. Kron (2012) CDK- dependent Hsp70 phosphorylation controls G1 cyclin abundance and cell cycle progression. Cell 151: 1308-1318. (Recommended by Faculty of 1000 Biology).
- He J, L. Xu, Z. Zou, N. Ueyama, H. Li, A. Kato, G. W. Jones and Y. Song (2012) Molecular dynamics simulation to investigate the impact of disulfide bond formation on conformational stability of chicken cystatin I66Q mutant. Journal of Biomolecular Structure and Dynamics DOI:10.1080/07391102.2012.721498.
- Gallagher L , R. A. Owens, S. K. Dolan, G. O’Keeffe, M. Schrettl, K. Kavanagh, G. W. Jones and S. Doyle (2012) The Aspergillus fumigatus protein GliK protects against oxidative stress and is essential for gliotoxin biosynthesis. Eukaryotic Cell DOI:10.1128/EC.00113-12.
- O’Hanlon K. A, G. P. Margison, A. Hatch, D. A. Fitzpatrick, R. A. Owens, S. Doyle and G. W. Jones (2012) Molecular characterisation of an adaptive response to alkylating agents in the opportunistic pathogen Aspergillus fumigatus. Nucleic Acids Research 40(16): 7806-7820.
- Shen M, J. Guan, L. Xu, Y. Yu, J. He, G. W. Jones and Y. Song (2012) Steered molecular dynamics simulation on the binding of appendant structure and helix-β2 in domain-swapped human cystatin C dimer. Journal of Biomolecular Structure and Dynamics October 30(6): 652-661.
- Carberry S, E. Molloy, S. Hammel, G. O'Keeffe, G. W. Jones, K. Kavanagh and S. Doyle (2012) Gliotoxin effects on fungal growth: mechanisms and exploitation. Fungal Genetics and Biology 49:302-312.
- Fitzpatrick D. A, J. O’Brien, C. Moran, N. Hasin, E. Kenny, P. Cormican, A. Gates, D.W. Morris and G. W. Jones (2011) Assessment of inactivating stop codon mutations in forty Saccharomyces cerevisiae strains: implications for [PSI+] Prion- Mediated Phenotypes. PLoS ONE 6(12):e28684.
- Medina E. M, G. W. Jones and D. A. Fitzpatrick (2011) Reconstructing the fungal tree of life using phylogenomics and a preliminary investigation of the distribution of yeast prion-like proteins in the fungal kingdom. Journal of Molecular Evolution. October Vol. 3-4: 116-133.
- Schrettl M, S. Carberry, K. Kavanagh, H. Haas, G. W. Jones, J. O’Brien, A. Nolan J. Stephens, O. Fenelon and S. Doyle (2010) Self- protection against gliotoxin- a component of the gliotoxin biosynthetic cluster GliT, protect Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathogens June 10;6(6):e1000952 (Recommended by Faculty of 1000 Biology).
- Guinan E, A. Blumlein, S.A. Cusack, C. Moran, H. M. Loovers and G. W. Jones (2009) Propagating prions- the role of molecular chaperones. Chapter 2, p33-50. In Prokaryotic and Eukaryotic Heat Shock Protein in Infectious Disease. A. Graham Pockley, M. Gabriella Santoro and Stuart K. Calderwood, editors.
- Guinan E and G. W. Jones (2009) The role of Hsp70 chaperone machinery in yeast prion propagation. Protein and Peptide Letters 16(6):583-6.
- Zhang H, H. M. Loovers, L.Q. Xu, M. Wang, P. J .E. Rowling, L. S. Itzhaki, W. Gong, J. M. Zhou, G. W. Jones and S. Perrett (2009) Alcohol oxidase (AOX1) from Pichia pastoris is a novel inhibitor of prion propagation and a potential ATPase. Molecular Microbiology 71(3): 702-716.
- Perrett S and G.W. Jones (2008) Insights into prion propagation. Current Opinion in Structural Biology 18(1): 52-9.
- Lian H. Y, H. Zhang, Z. R. Zhang, H. M. Loovers, G. W. Jones, P. J. E. Rowling, L. S. Itzhaki, J. M. Zhou and S. Perrett (2007) Hsp40 interacts directly with the native C-terminal region of the yeast prion protein Ure2 and inhibits formation of amyloid-like fibrils. Journal of Biological Chemistry 282(16): 11931-40.
- Loovers H. M, E. Guinan and G. W. Jones (2007)- Importance of Hsp70 ATPase domain in prion propagation. Genetics 175: 621- 630. (Featured in Issue Highlights)
- O’Connor D. I and G. W. Jones (2006) Chaperoning prions: the story unfolds. BIO TECH international; February/March issue, 18: 6-10.
- Lian H. Y, Y. Jiang, H. Zhang, G. W Jones, S. Perrett (2006) The Yeast Prion Protein Ure2: Structure, Function and Folding. BBA - Proteins and Proteomics 1764: 535- 545.
- Jones G. W and M. F. Tuite (2005) Chaperoning prions: the cellular machinery for propagating an infectious protein? BioEssays 27: 823- 832.
- Jones G, Y. Song, S. Chung and D. C. Masison (2004) Propagation of Saccharomyces cerevisiae [PSI+] prion is impaired by factors that regulate Hsp70 substrate binding. Molecular and Cellular Biology 24: 3928- 3937.
- Jones G. W, Y. Song and D. C. Masison (2003) Deletion of yeast HSP70 chaperone SSB causes hypersensitivity to guanidine toxicity and curing of [PSI+] prion by increasing guanidine uptake. Molecular Genetics & Genomics 269: 304- 311.
- Jung G and G. Jones (2003) Yeast Prions. J. of Biol. Macromol. 3: 41- 46.
- Jones G. W and D. C. Masison (2003) S. cerevisiae Hsp70 mutations affect [PSI+] prion propagation and cell growth differently and implicate Hsp40 and TPR co-chaperones in impairment of [PSI+]. Genetics 163: 495- 506.
- Piper P. W, G. W. Jones, D. Bringloe, N. Harris, M. MacLean and M. Mollapour (2002) The cause of the shortened replicative life span in prohibitin mutants of yeast appears to be defective mitochondrial morphology and segregation in old mother cells. Aging Cell 1: 149- 157.
- Jung G, G. Jones and D. C. Masison (2002) Amino acid residue of yeast Hsp104 chaperone critical for prion curing by guanidine and for prion propagation. Proceedings of the National Academy of Sciences U. S. A. 99: 9936- 9941.
- Jung G, G. W. Jones, R. D. Wegrzyn and D. C. Masison (2000) A role for cytosolic Hsp70 in yeast [PSI+] prion propagation and [PSI+] as a cellular stress. Genetics 156: 559- 570.
- Jones G. W, Hooley. P, Farrington. S. M, Shawcross. S. G and Strike. P (1999) Cloning and characterisation of the sagA gene of Aspergillus nidulans: a gene which affects sensitivity to DNA-damaging agents. Molecular & General Genetics 261: 251- 258.
- Jones G. W, S. H. Reed and R. Waters (1997) Characterisation of the rad14-2 mutant of Saccharomyces cerevisiae: implications for photoproduct recognition by the Rad14 protein. Yeast 13: 31- 36.
- Iwanejko L. A, C. M. Cotton, G. W. Jones, P. Strike and A. B. Tomsett (1996) Cloning and characterisation of nuvA, an Aspergillus nidulans gene involved in DNA repair and recombination. Microbiology-SGM 142: 505- 515.