Every time a cell divides, it must pull its chromosomes apart with surgical precision—and this project unpacks the molecular machinery that makes that happen. When this process goes wrong, cells end up with the wrong number of chromosomes, a condition called aneuploidy. That causes miscarriages, infertility, and birth defects, and it is a hallmark of cancer. The researcher has already shown that a region near the chromosome’s attachment point—the pericentromere—plays a bigger role in guiding and monitoring chromosome movement than previously appreciated. But the detailed molecular mechanisms remain unknown. This project uses budding yeast to uncover the fundamental principles, then extends the work into frog eggs to reveal how vertebrates add their own layers of regulation. The goal is to understand how chromosomes orient themselves correctly in both ordinary cell division (mitosis) and the specialised division that creates eggs and sperm (meiosis). This is fundamental science. It will not produce a drug or a diagnostic test tomorrow. But a deep molecular understanding of chromosome segregation is the foundation for eventually tackling the real-world consequences of aneuploidy—from improving fertility treatments to understanding how cancers become genetically unstable.
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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.
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