Stark, Michael

Regulation of Yeast Cell Growth and Division

My laboratory studies molecular mechanisms that regulate growth and division in the budding yeast Saccharomyces cerevisiae. A surprisingly large number of fundamental cellular processes are conserved between yeast and higher eukaryotes. The combination of the powerful classical and molecular genetic methodologies available, the well annotated genome and the ability to carry out sophisticated biochemistry and cell biology have turned budding yeast into a valuable model system in which to study conserved regulatory mechanisms.

A major current focus is 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 in yeast 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 modifications to U34 (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 and worms (C. elegans). 

Yeast Elp1 shows Hrr25-dependent phosphorylation and we have recently shown 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. We are currently dissecting the phosphoregulatory domain in Elp1 and trying to understand in molecular terms how Elp1 phosphorylation promotes Elongator function.

A second area of interest is in mechanisms that ensure chromosomes segregate properly when cells divide. Correct chromosome segregation is vital for maintenance of genome integrity, and gain or loss of chromosomes due to errors in chromosome segregation is a hallmark of cancer cells. The conserved protein kinase Ipl1/Aurora B is important as part of a correction mechanism that ensures sister chromatids become attached to microtubules from opposite spindle poles during mitotic metaphase – a state termed chromosome bi-orientation – so that they are pulled in opposite directions during anaphase when chromosomes segregate. Ipl1 kinase activity is regulated by its association with other components of the ‘chromosome passenger complex’ – Sli15 (INCENP), Bir1 (Survivin) and Nbl1 (Borealin) – and we are using yeast to understand how these regulatory subunits control Ipl1 kinase activity during chromosome bi-orientation. We would like to understand how tension regulates Ipl1-dependent phosphorylation of its targets at the kinetochore and our current focus is on the role of Bir1, part of the Ipl1-associated chromosome passenger complex that like Ipl1 is required for chromosome biorientation.

I am currently CLS Programme Manager for the new MRes in Cancer Biology run jointly by the College of Life Sciences and College of Medicine, Dentistry & Nursing at Dundee University. Within the MRes Course itself I act as tutor for two students, deliver 6 lectures in the Introductory week and am heavily involved in journal club sessions, student assessment and recruitment of new students to the Programme, all of who receive an interview either in person or via Skype. I have a variety of related administrative responsibilities that include membership of the School of Learning & Teaching Board, the CLS Taught Postgraduate Committee and the College Academic Standards Committee and I am also involved in the development of the new Undergraduate curriculum for Life Sciences, including acting as Convener for the new Gene Regulation & Expression Module that forms part of the new Core Level 3 structure.

Within the Molecular Biology Degree Board I act as Course Tutor to a quarter of our Level 4 students and I am Coordinator of the Cell Cycle Course Unit in the Life Sciences Level 4 portfolio. I present 4 lectures in total in this Course Unit, together a two-hour session in the Statistics & Numeracy Unit. I typically run 1 Level 4 Honours research project annually.

At Level 3 I teach the protein biosynthesis section of the BI31022 Genome Sciences module, a section on fungal pathogens and antifungal agents in the BI32052 Molecular Microbiology & Immunology module and the cell cycle section of the BI32032 Molecular Cell Biology module (11 lectures altogether), and run a 5-day practical class on gene cloning and manipulation.

I teach two specialist lectures in the BS21002 The Cell and the Gene module of the new Level 2 Life Sciences curriculum. I also offer a Student Selected Component on the Human Genome Project to four Phase 1 medical students each year.

I trained in Biochemistry at the University of Leicester, working on bacterial ribosomes and continuing this theme through a postdoctoral position with Albert Dahlberg at Brown University in the USA. I began working with yeast in 1983 at the Leicester Biocentre, establishing my own group at Dundee in 1987 to study aspects of yeast cell growth and division. Early projects focussed on an essential role of calmodulin at the yeast spindle pole body (SPB) and on the roles and regulation of yeast protein phosphatases, principally PP1 and PP2A. Recent work has focussed on the regulation of role of Ipl1 (Aurora B) kinase and on Elongator, a protein complex required for tRNA wobble uridine modification in eukaryotes.