Website University of Dundee
- Funding – BBSRC funded 4 year studentship, providing tuition fees, training/research costs and an annual stipend at the UKRI rate, currently £21,805
- Start Date – September 2027
- Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline
To maintain genetic integrity, eukaryotic cells must correctly segregate chromosomes to opposite spindle poles during mitosis. This process relies on the fine-tuned interaction between spindle microtubules (MTs) and the kinetochore. For correct chromosome segregation, two kinetochores on sister chromatids must interact with spindle MTs extending from opposite spindle poles (chromosome biorientation) before chromosome segregation (PMID 35563768). For this process to be robust, error correction is required, through which aberrant kinetochore-MT interactions are removed by Aurora B kinase. The Aurora B kinase acts by phosphorylating the outer kinetochore components and weakening the kinetochore-MT interactions. If error correction is disrupted, as is often the case in cancer cells, one observes chromosome instability, which is a major cause of chemotherapy resistance and poor patient prognosis (PMID 19879145).
This project aims to uncover detailed mechanisms of error correction in normal cells. It is known that, when chromosome biorientation is established, tension is applied to the kinetochore-MT interaction, stabilising biorientation. However, it is still unclear how Aurora B ceases to promote error correction under tension (PMID 38305688). We use budding yeast as a model organism because error-correction mechanisms are fundamentally conserved from yeast to humans.
The Ndc80 and Dam1 complexes (Ndc80C and Dam1C) are two major outer kinetochore components. The two complexes interact with each other, critically regulated during error correction to achieve biorientation. Recent structural studies revealed how Ndc80C and Dam1C interact with each other on MTs in vitro (PMID 38060647, 36883282). However, it is still unclear how they are dynamically regulated by mechanical tension and Aurora B.
The PhD student will address this question using chemical crosslinks. They will identify novel Ndc80C-Dam1C-MT interactions and address how these change when Aurora B is defective and when cells are unable to apply tension on kinetochore-MT interactions. They will also generate mutants to disrupt Ndc80C-Dam1C-MT interactions and investigate the outcome on chromosome biorientation using live-cell imaging. The project will be carried out in collaboration with the Sknepnek group, which is developing a computational model of kinetochore-MT interaction. Based on this model, we will design chemical crosslink experiments.
Throughout this project, the PhD student will learn molecular genetics, advanced biochemistry, live-cell imaging and how to collaborate with computational biologists. The project will find an answer to a fundamental question in cell biology, i.e. how cells find the right chromosomes for segregation in mitosis, and will also provide insights into how chromosomal instability arises in cancer cells.
Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education
How to apply
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