Molecular mechanisms of genome structure and segregation

Genome segregation is an indispensable aspect of life. During mitosis, chromosomes are reorganised dramatically into discrete cylindrical entities. Chromosome refolding facilitates disentanglement of sister-chromatids, permitting their even distribution between two daughter cells, and provides resilience to the forces of genome segregation. Structural maintenance of chromosomes (SMC) complexes, such as condensin and cohesin, are thought to organise chromosomes through into chromatin loops. I propose to use cryo-electron microscopy and cryo-electron tomography to develop an integrative structural-biology program that bridges scales from molecules to entire chromosomes to understand the mechanism of mitotic genome folding and how this contributes to chromosome segregation. We will ask: Aim 1. What are the molecular mechanisms underlying mitotic chromosome organisation by human condensin-I/II? Aim 2. How are SMC complexes enriched at the kinetochore, and how do they support functional centromere structure to facilitate genome segregation? Aim 3. What is the molecular architecture of mitotic human chromosomes, and how is this achieved at a mechanistic level? Using my expertise as a structural biologist, we will define principles of mitotic chromosome organisation relevant across eukaryotes, how chromosome structure relates to function, and will provide a platform to study how defects in these processes leads to aneuploidy and consequent pathologies.