Mechanisms orienting chromosomes in mitosis and meiosis. (360G-Wellcome-107827_Z_15_Z)

The overall theme of my research is to understand molecular mechanisms of chromosome segregation. Altered chromosome number (aneuploidy) causes miscarriages, infertility and birth defects and is a characteristic of cancer. During mitosis, duplicated sister chromatids are pulled apart to produce identical daughter cells. Meiosis generates gametes through two consecutive segregation events: maternal and paternal chromosomes are separated in meiosis I and sister chromatids are segregated during mei osis II. Accordingly, sister kinetochores attach to microtubules from opposite poles in mitosis and meiosis II (bioriented), but to the same pole during meiosis I (monooriented). How these distinct orientations are specified and safeguarded remains poorly understood. We previously demonstrated that the chromosomal region surrounding the kinetochore, the pericentromere, plays multiple underappreciated roles in directing and monitoring chromosome segregation. I now propose to build on these discov eries and elucidate the molecular underpinnings of the interplay between pericentromeres and kinetochores to understand how chromosomes are oriented in mitosis and meiosis. We will use budding yeast to uncover fundamental mechanisms; to reveal conserved principles and vertebrate-specific regulation we will initiate studies on Xenopus oocytes. Specifically we aim to: (1) Determine how the pericentromere is functionally and geometrically organised to orient chromosomes; (2) Understand how the peri centromere acts as a signalling platform to monitor and regulate chromosome segregation; and (3) Reveal the adaptations to kinetochores which direct the specialized pattern of chromosome segregation during meiosis. Ultimately, we will gain an in-depth molecular knowledge of how kinetochores and pericentromeres confer directionality to chromosome movement in mitosis and meiosis.