Professor Mike Stark
Emeritus Professor of Yeast Molecular Biology
Gene Regulation and Expression, School of Life Sciences
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. 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) PMID: 31147620 Abstract View Publication
- 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. 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) PMID: 30916349 Abstract View Publication
- 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. The Type VI secretion system deploys anti-fungal effectors against microbial competitors Nature Microbiol. 3: 920-931 (doi 10.1038/s41564-018-0191-x) PMID: 30038307 Abstract View Publication
- Makrantoni V, Ciesiolka A, Lawless C, Fernius J, Marston A, Lydall D, Stark MJR. A Functional Link Between Bir1 and the Saccharomyces cerevisiae Ctf19 Kinetochore Complex Revealed Through Quantitative Fitness Analysis. PMID: 28754723 Abstract View Publication
- Abdel-Fattah, W., Jablonowski, D., Di Santo, R., Thuring, K. L., Scheidt, V., Hammermeister, A., Ten Have, S., Helm, M., Schaffrath, R. and Stark, M. J Phosphorylation of Elp1 by Hrr25 is required for Elongator-dependent tRNA modification in yeast. PMID: 25569479 Abstract View Publication
|Fellow of the Royal Society of Biology||2011|