Project Title: The immediate and long term consequences of end on conversion failure
Summary: During cell division, the proper attachment of microtubules to chromosomes is important for the accurate segregation of chromosomes. Chromosome-microtubule attachment is facilitated by a multiprotein structure - the kinetochore - that assembles on the centromeric region of DNA. Kinetochores are first captured along the lateral walls of microtubules, and then tethered to the ends of microtubules by a multi-step process called the end-on conversion process. Only when kinetochores are tethered to microtubule-ends, microtubule growth and shrinkage can be translated into chromosome pulling and pushing forces, respectively. As these forces ensure correct chromosome alignment and sister chromatid separation, end-on conversion is vital to prevent the loss or gain of chromosomes, a state called aneuploidy. Generally, aneuploidy is not compatible with cell viability, and causes large scale metabolic changes. However, aneuploidy is present at very high levels in both solid tumours and haematological malignancies. This suggests the presence of chromosome variations provides a selective advantage to the cell, but also that cancer cells have mechanisms to cope with the metabolic changes that aneuploidy drives. To obtain quantitative and molecular insight into how aneuploidy and growth advantage coexist, I aim to characterise the consequences of end-on conversion failure; DNA damage, cell cycle changes and protein homeostasis effects. By comparing my findings with pancreatic tumour samples, my study aims to expand our fundamental understanding of how cell cycle, protein homeostasis, genome integrity are maintained and highlight where this may break down in aggressive pancreatic tumours.