Structure and Function of a Eukaryotic Centromere

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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 identified a novel structure composed of cohesin, condensin and pericentric DNA that encompasses the spindle microtubules in metaphase in the model organism, S. cerevisiae. 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. We have recently discovered a mechanism in which centromere chromatin loops generate an extensional force sufficient to release nucleosomes proximal to the spindle axis. The discovery comes from applying thermodynamic principles to the close packing of radial loops in the centromere. Radial loops are recognized as the structural basis for the organization of chromosomes in nearly all eukaryotes. The density of loops has biological consequences that transcend the centromere. Tension forces from closely packed loops impact the affinity of DNA binding proteins and thus the biochemistry of transcriptional control as well as replication. Our goal is to extend our understanding of how DNA loops are built, the consequences of close packing, and the implications in regulating access to the genome. We use the budding yeast with a combination of genetics, quantitative imaging, in vivo biophysics and computational modeling. RELEVANCE (See instructions); The genome of every organism is packaged into chromosomes that must be replicated and segregated with exquisite fidelity. 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 in mitosis, a conserved process in all eukaryotes.