Professor Mike Stark FRSB
The availability of powerful classical and molecular genetic methodologies, a well annotated genome and the ability to carry out sophisticated biochemistry and cell biology make the yeast Saccharomyces cerevisiae a valuable model organism in which to study conserved regulatory mechanisms. A surprisingly large number of fundamental cellular processes are conserved between yeast and higher eukaryotes and I am interested in studying those molecular mechanisms that regulate growth and division using Saccharomyces cerevisiae as a model system.
My recent research has focused on Elongator, a conserved, six-subunit protein complex. Although Saccharomyces cerevisiae Elongator is non-essential for growth in the laboratory, it is essential for mammalian development and mutations in its Elp1 subunit are associated with Familial Dysautonomia, a neurodevelopmental disease. Over the past decade a variety of roles have been proposed for Elongator, but the principal and possibly only role of Elongator is to promote two related chemical modifications to the uridine residue that is present at the anticodon ‘wobble’ position (U34) in a subset of tRNAs. These U34 modifications (termed mcm5U and ncm5U) are required for wobble uridine-containing tRNAs to function efficiently in protein synthesis, and Elongator’s role in wobble uridine modification is conserved in plants, worms (C. elegans) and mammals.
Yeast Elp1 shows Hrr25-dependent phosphorylation and we have shown recently that this is required for Elongator functionality. Hrr25, a yeast casein kinase I orthologue, directly phosphorylates Elp1 and Elongator-dependent tRNA wobble uridine modification depends on phosphorylation of the Hrr25 sites along with other, adjacent phosphorylation sites that are not directly phosphorylated by Hrr25. The phosphorylated region is adjacent to a domain in Elp1 that we have shown to bind tRNA and we would like to understand, in molecular terms, how these phosphoregulatory and tRNA binding domains in Elp1 cooperate to promote wobble uridine modification, which is likely to be catalyzed by Elongator’s Elp3 subunit.
Pinneh, E. C., Mina, J. G., Stark, M. J. R., Lindell, S. D., Lumen, P., Knight, M. R., Steel, P. G. and Denny, P. W. (2019). The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. Scientific Reports 9: 8083 (doi.org/10.1038/s41598-019-44544-1)
Krutyhołowa, R., Hammermeister, A., Zabel, R., Abdel-Fattah, W., Reinhardt-Tews, A., Helm, M., Stark, M. J. R., Breunig, K. D., Schaffrath, R. and Glatt, S. (2019). Kti12, a PSTK-like tRNA dependent ATPase essential for tRNA modification by Elongator. Nucleic Acids Research 47: 4814-4830 (doi.org/10.1093/nar/gkz190)
Trunk, K., Peltier, J., Liu, Y. -C., Dill, B. D., Walker, L., Gow, N. A. R., Stark, M. J. R., Quinn, J., Strahl, H., Trost, M. and Coulthurst, S. J. (2018). The Type VI secretion system deploys anti-fungal effectors against microbial competitors. Nature Microbiol. 3: 920-931 (doi 10.1038/s41564-018-0191-x)
Makrantoni, V., Ciesiolka, A., Lawless, C., Fernius, J., Marston, A., Lydall, D., and Stark, M.J.R. (2017). A Functional Link Between Bir1 and Saccharomyces cerevisiae Ctf19 Kinetochore Complex Revealed Through Quantitative Fitness Analysis. G2 (Bethesda), 7(9), 3203-3215 view paper
Abdel-Fattah, W. R., Jablonowski, D., Di Santo, R. T. A., Thüring, K. L., Scheidt, V., ten Have, S. M., Helm, M., Schaffrath, R. and Stark, M. J. R. (2015). Phosphorylation of Elp1 by Hrr25 is required for Elongator-dependent tRNA modification in yeast. PLoS Genetics e1004931. View Paper
Di Santo, R., Bandau, S. and Stark, M. J. R. (2014). A conserved and essential basic region mediates tRNA binding to the Elp1 subunit of the Saccharomyces cerevisiae Elongator complex. Mol Microbiol. 92, 1227–1242. View Paper
Makrantoni, V., Corbishley, S. J., Rachidi, N., Morrice, N. A., Robinson, D. A. and Stark, M. J. R. (2014). Phosphorylation of Sli15 by Ipl1 is important for proper CPC localization and chromosome stability in Saccharomyces cerevisiae. PLoS ONE 9, e89399. doi:10.1371/journal.pone.0089399 View Paper
Uthman, S., Bär, C., Scheidt, V., Liu, S., ten Have, S., Giorgini, F., Stark, M. J. R. and Raffael Schaffrath, R. (2013). The amidation step of diphthamide biosynthesis in yeast requires DPH6, a gene identified through mining the DPH1-DPH5 interaction network. PLoS Genet 9, e1003334. View Paper
Keating, P., Rachidi, N., Tanaka, T. U. and Stark, M. J. R. (2009). Ipl1-dependent phosphorylation of Dam1 is reduced by tension applied on kinetochores. J. Cell Sci. 122, 4375-4382. View Paper
Makrantoni, V. and Stark, M. J. R. (2009). Efficient chromosome bi-orientation and the tension checkpoint in Saccharomyces cerevisiae both require Bir1. Mol. Cell. Biol. 29, 4552-4562. View Paper
Lain, S., Hollick, J. J., Campbell, J., Staples, O., Higgins, M., Aoubala, M., McCarthy, A., Appleyard, V., Murray, K. E., Baker, L., Thompson, A., Mathers, J., Holland, S. J., Stark, M. J. R., Pass, G., Woods, J., Lane, D. P. and Westwood, N. J. (2008). Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13, 454-463. View Paper
Fox, G. C., Shafiq, M., Briggs, D. C., Knowles, P.P., Collister, M., Didmon, M., Makrantoni, V., Dickinson, R., Hanrahan, S., Totty, N., Stark, M. J. R., Keyse, S. M. and McDonald, N. Q. (2007).
Redox-mediated substrate recognition by Sdp1 defines a new group of tyrosine phosphatases. Nature 447, 487-492. (doi:10.1038/nature05804). View Paper
Tanaka, T., Rachidi, N., Janke, C., Pereira, G., Galova, M., Schiebel, E., Stark, M. J. R. and Nasmyth, K. (2002). Evidence that the Ipl1/Sli15 (Aurora kinase/INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108, 317-329. View Paper