Molecular Mechanisms of Centromere Inheritance and Kinetochore Function

Accurate chromosome segregation during cell division is essential for genome integrity and relies on the physical coupling of chromosomes to spindle microtubules mediated by kinetochores. The kinetochores are large proteinaceous structures assembled on a specific chromosomal locus known as the centromere, defined by the enrichment of CENP-A containing nucleosomes. Defective centromere/kinetochore function results in chromosome segregation errors that can contribute to genomic instability implicated in cancer. Therefore, error-free chromosome segregation depends on i) the maintenance of centromeric chromatin at the right place and ii) the kinetochore’s ability to establish microtubule-attachments capable of driving chromosome separation. While we know most molecular players regulating these processes, structure-based mechanistic details of how they exert their function remain poorly understood. Taking advantage of my expertise in combining high-resolution structural data with biochemical/biophysical and cell-based assays, I propose to elucidate the structural basis for: (1) how players of the CENP-A deposition pathway are targeted to centromeres and how they facilitate CENP-A deposition and; (2) how kinetochore microtubule-binding factors bind microtubules and harness the spindle-associated force to drive chromosome segregation. The outcome of this work will reveal the mechanistic details of how intricate intermolecular interactions achieve centromere inheritance and kinetochore function.