Project No. 2486

STANDARD PROJECT

Primary Supervisor

Dr Karen Wing Yee Yuen – University of Southampton

Co-Supervisor(s)

Dr Helfrid Hochegger- University of Sussex

Summary

Aurora B is a conserved kinase that has multiple functions in mitosis.

1. Rationale and importance: Aurora B is a conserved kinase that has multiple functions in mitosis. Its most well known function is serving as a Chromosome Passenger Complex (CPC) component, which corrects microtubule misattachments. However, the number of substrates known for Aurora B is limited, including only histone H3, CENP-A, and condensin I non-SMC subunits. One of the limitation is that there is no systematic, genome-wide approach to identify changes in the phosphor-proteome when Aurora B is inactivated.

2. Approaches to be used: Using a 5-second fast-acting, temperature-sensitive mutant of air-2/Aurora B in C. elegans embryos, the Yuen Lab, in collaboration with Xumin Zhang in Fudan University, have performed a phosphor-proteomics analysis to compare the phosphorylated peptide profiles in wild-type and air-2 mutant after temperature upshift. We have identified 5106 phospho-proteins that are down-regulated in air-2 mutant. These are potential novel AIR-2 phosphorylation substrates. The PhD studnet will use a combination of in vitro and in vivo studies to validate prioritized substrates and the specific phosphorylation sites, and investigate the cellular consequences lacking phosphorylation.

3. Areas of potential impact: As a kinase involved in cell division, overexpression of Aurora B has been shown to lead to aneuploidy and chromosomal instability (CIN). Inhibitors for Aurora B, have been intensively investigated for their effects on CIN. However, due to the multi-functions nature of Aurora B, the effects could be pleiotropic. By identifying novel substrates of Aurora B, it is possible to dissect the functions. The results of this project will be instrumental to the understanding of the rule of life and eukaryotic cell cycle regulation. The phosphorylation function of Aurora B will showcase how cells use post-translational modifications to regulate the timing and order of events in mitosis. This project can provide a framework of how to systematically dissect the functions of kinase unbiasedly.

4. Candidate qualities suitable for the project: Candidates with molecular biology exposure and interest in cellular imaging, bioinformatic and proteomic analyses will be highly suitable for project. Candidates should be driven and initiative.