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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM032238-26
Application #
8309990
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Deatherage, James F
Project Start
1983-07-01
Project End
2016-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
26
Fiscal Year
2012
Total Cost
$482,183
Indirect Cost
$150,567
Name
University of North Carolina Chapel Hill
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lawrimore, Josh; Aicher, Joseph K; Hahn, Patrick et al. (2016) ChromoShake: a chromosome dynamics simulator reveals that chromatin loops stiffen centromeric chromatin. Mol Biol Cell 27:153-66
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
Tsabar, Michael; Haase, Julian; Harrison, Benjamin et al. (2016) A Cohesin-Based Partitioning Mechanism Revealed upon Transcriptional Inactivation of Centromere. PLoS Genet 12:e1006021
Mishra, Prashant K; Ciftci-Yilmaz, Sultan; Reynolds, David et al. (2016) Polo kinase Cdc5 associates with centromeres to facilitate the removal of centromeric cohesin during mitosis. Mol Biol Cell 27:2286-300
Falk, Jill Elaine; Tsuchiya, Dai; Verdaasdonk, Jolien et al. (2016) Spatial signals link exit from mitosis to spindle position. Elife 5:
Ohkuni, Kentaro; Takahashi, Yoshimitsu; Fulp, Alyona et al. (2016) SUMO-Targeted Ubiquitin Ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin. Mol Biol Cell :
Vasquez, Paula A; Hult, Caitlin; Adalsteinsson, David et al. (2016) Entropy gives rise to topologically associating domains. Nucleic Acids Res 44:5540-9
Bloom, Kerry (2015) Anniversary of the discovery/isolation of the yeast centromere by Clarke and Carbon. Mol Biol Cell 26:1575-7
Stephens, Andrew D; Snider, Chloe E; Bloom, Kerry (2015) The SUMO deconjugating peptidase Smt4 contributes to the mechanism required for transition from sister chromatid arm cohesion to sister chromatid pericentromere separation. Cell Cycle 14:2206-18
Calderon, Christopher P; Bloom, Kerry (2015) Inferring Latent States and Refining Force Estimates via Hierarchical Dirichlet Process Modeling in Single Particle Tracking Experiments. PLoS One 10:e0137633

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