Structure and Function of a Eukaryotic Centromere

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): 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.