Kinetochore self-correction mechanisms underlying faithful chromosome segregation in humans

Errors in human chromosome segregation are infrequent yet devastating. Aneuploidy, in which entire chromosomes are gained or lost, is a hallmark of cancer, ageing and reproductive failure. To minimise errors, dividing cells assemble a bipolar guidance scaffold, the spindle, and connect each chromosome to its own self-correcting molecular engine, the kinetochore. The remarkable feature of the kinetochore is that they monitor their own attachment state and use this information to eliminate mis-attachments, activate/deactivate checkpoints and direct chromosome movements. How kinetochore achieve this remains mysterious. Previously, kinetochore self-correction was thought to occur only during early mitosis, but we have recently shown that kinetochore self-correction persists deep into anaphase when the chromosomes are being segregated. I propose to understand both pre- and post-segregation self-correction mechanisms by harnessing cutting-edge live cell imaging, computational tools and genome engineering with a focus on the following challenges in the field:

1. Unravel how kinetochores sense and correct their own function.

2. Define how pre- and post-anaphase error correction control the risk of aneuploidy.

3. Measure the forces human kinetochores generate in living cells and understand how kinetochores respond mechanically and functionally to force.