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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Molecular Genetics C Study Section (MGC)
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Deatherage, James F
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University of North Carolina Chapel Hill
Schools of Arts and Sciences
Chapel Hill
United States
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Salmon, Edward D; Bloom, Kerry (2017) Tension sensors reveal how the kinetochore shares its load. Bioessays 39:
Lawrimore, Josh; Barry, Timothy M; Barry, Raymond M et al. (2017) Microtubule dynamics drive enhanced chromatin motion and mobilize telomeres in response to DNA damage. Mol Biol Cell 28:1701-1711
Lawrimore, Josh; Friedman, Brandon; Doshi, Ayush et al. (2017) RotoStep: A Chromosome Dynamics Simulator Reveals Mechanisms of Loop Extrusion. Cold Spring Harb Symp Quant Biol :
Haase, Karen P; Fox, Jaime C; Byrnes, Amy E et al. (2017) Stu2 uses a 15 nm parallel coiled coil for kinetochore localization and concomitant regulation of the mitotic spindle. Mol Biol Cell :
Hult, Caitlin; Adalsteinsson, David; Vasquez, Paula A et al. (2017) Enrichment of dynamic chromosomal crosslinks drive phase separation of the nucleolus. Nucleic Acids Res 45:11159-11173
Bloom, Kerry (2017) Liberating cohesin from cohesion. Genes Dev 31:2113-2114
Bloom, Kerry; Costanzo, Vincenzo (2017) Centromere Structure and Function. Prog Mol Subcell Biol 56:515-539
Tsabar, Michael; Haase, Julian; Harrison, Benjamin et al. (2016) A Cohesin-Based Partitioning Mechanism Revealed upon Transcriptional Inactivation of Centromere. PLoS Genet 12:e1006021
Falk, Jill Elaine; Tsuchiya, Dai; Verdaasdonk, Jolien et al. (2016) Spatial signals link exit from mitosis to spindle position. Elife 5:
Suzuki, Aussie; Badger, Benjamin L; Haase, Julian et al. (2016) How the kinetochore couples microtubule force and centromere stretch to move chromosomes. Nat Cell Biol 18:382-92

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