PhD-How cells find the right chromosomes: the dynamic regulation of kinetochore-microtubule interactions for biorientation
PhD @University of Dundee posted 3 days agoJob Description
- Funding – self-funded/externally sponsored applicants (PhD Fees can be found here)
- Applications are accepted year round
- Standard Entry dates – January and September
- 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 interaction between spindle microtubules (MTs) and the kinetochore – a large protein complex providing a major microtubule attachment site on a chromosome. 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, error correction is required through which aberrant kinetochore-MT interactions are removed by Aurora B kinase that phosphorylates outer kinetochore components and weakens kinetochore-MT interactions. The error correction process is defective in many cancer cells, leading to chromosome instability, which is a major cause of chemotherapy resistance and poor prognosis of cancers (PMID 19879145).
To understand the mechanisms of chromosome instability in cancer cells, we should first uncover detailed mechanisms of error correction in normal cells. It is known that, when chromosome biorientation is established, tension is applied to kinetochore-MT interaction, stabilising it to stop the error correction. However, there remains a critical knowledge gap in how Aurora B ceases promoting error correction when tension is applied (PMID 38305688). One model suggests that, when tension is applied, Aurora B spatially separates from outer kinetochore components and therefore cannot phosphorylate them (PMID 37788666). Another model suggests that, with tension, kinetochores undergo conformational changes, which overcomes the action of Aurora B (PMID 35443757). We are testing these models by investigating the dynamic regulations of the kinetochore-MT interface. We use budding yeast as a model organism because basic mechanisms for error correction are conserved from yeast to humans.
The Ndc80 complex (Ndc80c) and the Dam1 complex (Dam1c) are two major outer kinetochore components. The two complexes interact with each other, which is critically regulated during error correction to achieve biorientation. The recent structural studies revealed how Ndc80C and Dam1C interact with each other on MTs in vitro (PMID 38060647, 36883282). However, it is still unclear whether such interactions also occur within cells and how they are regulated by Aurora B and by the tension.
In this PhD project, the student will address these questions using chemical crosslinks. Our preliminary data suggest that chemical crosslinks indeed detect Ndc80C-Dam1C interactions within cells (unpublished). The student will identify novel Ndc80C-Dam1C interactions and address how they change when Aurora B is defective and when cells are unable to apply tension on kinetochore-MT interactions. They will also make mutants to disrupt the Ndc80C-Dam1C interactions and investigate the outcome in 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 chromosome 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
Please contact the principal project supervisor to discuss your interest further, see supervisor details below.
For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk
