Impact of microtubule dynamics on cell mechanics, cell division and chromosome segregation

Chromosome segregation errors lead to aneuploidy, a condition associated with cancer and developmental abnormalities. Therefore, a critical question in biology is how potential chromosome segregation errors are corrected prior to cell division. In this project, you will study the impact of microtubule dynamics in preventing aneuploidy.

This work will study the action of microtubule depolymerases from the molecular (supervisor Friel) to the cellular (supervisor Huett) scale and in terms of their effect on the mechanical properties of cells (supervisor Wright). The focus will be on the human microtubule depolymerising kinesin, MCAK, which is a major direct regulator of microtubule dynamics during cell division. Reduction in MCAK activity in cells results in hyperstabilised chromosome-microtubule attachments leading to defects in chromosome segregation. The converse, excessive MCAK activity, leads to loss of microtubule stability and defects in capture and alignment of chromosomes. Therefore, the activity of MCAK must be tightly controlled to allow correct chromosome segregation.

You will leverage a bank of well characterised MCAK variants created in the Friel lab which possess a range of microtubule depolymerisation activity from 100-fold below to 10-fold above wild-type levels. This provides the ability to titrate microtubule depolymerising activity in cells with a precision not previously possible. Using cells, which possess different levels of microtubule depolymerase activity, you will dissect the relationship between microtubule stability, the mechanical properties of the cell, the progress of cell division and the fidelity of chromosome segregation. You will use state of the art fluorescence imaging, computational image analysis methods and optical trapping techniques to observe and quantify the effect of tuning depolymerase activity on chromosome segregation, cell division and the mechanical properties of the cell.

Using these biological tools and biophysical techniques, you will produce a suite of data that will enhance our knowledge of the effect of microtubule depolymerising kinesins on the mechanical properties of cells, on cell division and on the fidelity of chromosome segregation. Introducing well understood MCAK variants to cells, provides an elegant system to determine the consequences of perturbing microtubule depolymerisation activity in defined ways. Regulation of microtubule stability is crucial throughout the cell cycle. Disregulation of the microtubule depolymerisng kinesin, MCAK, is observed in various cancer cell types and overexpression of MCAK is known to underlie certain cases of resistance to the anticancer drug, taxol. This work will generate insights into the impact of alterations in microtubule stability on conditions such as cancer and aneuploidy.

The University of Nottingham is one of the world’s most respected research-intensive universities, ranked 8th in the UK for research power (REF 2014). Students studying in the School of Life Sciences will have the opportunity to thrive in a vibrant, multidisciplinary environment, with expert supervision from leaders in their field, state-of-the-art facilities and strong links with industry. Students are closely monitored in terms of their personal and professional progression throughout their study period and are assigned academic mentors in addition to their supervisory team. The School provides structured training as a fundamental part of postgraduate personal development and our training programme enables students to develop skills across the four domains of the Vitae Researcher Development Framework (RDF). During their studies, students will also have the opportunity to attend and present at conferences around the world. The School puts strong emphasis on the promotion of postgraduate research with a 2-day annual PhD research symposium attended by all students, plus academic staff and invited speakers.