The long term goal of my laboratory is to understand the mechanisms responsible for chromosome segregation. Accurate chromosome segregation is essential for normal growth and development. Errors in segregation lead to Down's syndrome, the most frequent inherited birth defect, pregnancy loss, and cancer. Age-related errors in maintaining the ends of chromosomes (telomeres) have been long recognized as a cause of replicative senescence. More recently, loss of centromere cohesin and the inability to bind meiotic chromosomes together has been directly linked to mechanisms responsible for the maternal age affect wherein the probability of a trisomic pregnancy increases from 2% to 35% by the age of 40. We have recently identified a barrel structure composed of cohesin, condensin and pericentric DNA that encompasses the spindle microtubules in metaphase in the model organism, S. cerevisiae [1]. The chromatin barrel acts as a spring in mitosis that contributes to force balance mechanisms when chromosome attachment and alignment are monitored by the spindle checkpoint. In addition, the barrel contributes to the regulatory function of the inner centromere and the spindle checkpoint, including the Bub1 kinase. The spindle checkpoint is the major signal transduction pathway responsible for chromosome segregation fidelity and coordinating cell cycle progression with mitosis. A major question in the field is how this checkpoint monitors chromosome bi-orientation on the mitotic spindle. Our goal is to extend our understanding of centromeric cohesin and the spindle checkpoint using the budding yeast with a combination of genetics, quantitative imaging, in vivo biophysics and computational modeling.
The genome of every organism is packaged into chromosomes that must be replicated and segregated with exquisite fidelity. The cell builds a microtubule-based machine, known as the mitotic spindle that connects to each chromosome at the centromere. The protein complex that links microtubules to the centromere is the kinetochore. The process of attaching chromosomes to microtubules and orienting sister chromatids to each spindle pole is inherently error-prone. The cell has developed a powerful signaling system (the spindle assembly checkpoint) that coordinates events at the kinetochore to cell cycle progression, thus ensuring chromosomes are properly oriented prior to chromosome segregation in anaphase. Despite significant progress on interaction of the kinetochore with microtubules, there is relatively little information on the structure and function of centromeric chromatin in mitosis. We have discovered a new structure composed of cohesin and condensin that surrounds the mitotic spindle. Our work will examine how pericentric chromatin is organized in the spindle and how it functions to balance microtubule-based forces.
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