Mechanisms governing the formation and correction of erroneous kinetochore-microtubule attachments

Cell division is an essential but risky business. Duplicated chromosomes are segregated between the two new cells with the aid of the spindle, a bipolar guidance scaffold, which is connected to each chromosome through the kinetochore. Kinetochores are self-correcting molecular machines that generate forces to move chromosomes. They are also able to identify and eliminate incorrect kinetochore-spindle attachments. This is key as persistence of incorrect attachments can lead to new cells gaining or losing entire chromosomes, known as aneuploidy, which is associated with reproductive failure, ageing, and cancer. In this project the student will investigate the life cycle of incorrect attachments with a focus on syntelics; in this situation the kinetochores on a duplicated chromosome pair are attached to the same spindle pole (rather than opposite poles). They will track kinetochore conformation, attachment, and phosphorylation status, and create a model of events from creation to resolution of these incorrect attachments. To achieve this, the student will utilise and gain extensive experience in:
Advanced fluorescent microscopy techniques, including fixed cell spinning disk confocal microscopy and live cell lattice light sheet microscopy
Development and use of computational modelling and analysis pipelines
Essential molecular biology techniques
We expect this combination of cell and computational biology to provide new insights into how human cells ensure they maintain the correct number of chromosomes.