The flawless execution of cell division is essential to the generation and survival of all organisms. During every cell cycle, chromosomes must be accurately partitioned to daughter cells to prevent genomic instability and aneuploidy, a hallmark of all tumors and many birth defects. Our goal is to elucidate the mechanisms that ensure accurate chromosome segregation and therefore contribute to understanding the basis of human disease. We are studying chromosome segregation in budding yeast because it is amenable to both genetic and biochemical analyses and the mechanism of chromosome segregation is fundamentally conserved. Chromosome segregation requires that the kinetochores of duplicated chromosomes (sister chromatids) biorient such that they bind to microtubule (MTs) arising from opposite spindle poles. Although it is essential that every pair of sister kinetochores make bioriented MT-kinetochore attachments, the mechanisms that establish, maintain, and correct errors in biorientation are still largely unknown. The only protein known to be essential for kinetochore biorientation is the conserved IpH (Aurora B) protein kinase whose localization and activity is regulated by the SIM 5 (INCENP) protein and opposed by Glc7, the catalytic subunit of protein phosphatase I. We have identified additional genes that likely regulate biorientation because they become essential when IpM function is impaired. We will therefore characterize the role of these genes in biorientation and identify the mechanisms that they use to regulate biorientation. Although IpH and Glc7 are critical for kinetochore biorientation, few molecular targets of these enzymes have been identified. We have therefore developed a method to purify kinetochores that will allow us to identify post-translational modifications associated with these enzymes and biorientation. Finally, we will take complementary genetic and biochemical approaches to understand how the activities of IpH and Glc7 are spatially and temporally coordinated to ensure that biorientation defects are detected and corrected. Taken together, these studies should lead to a better understanding of chromosome segregation and the maintenance of genomic stability in all eukaryotes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Deatherage, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Geyer, Elisabeth A; Miller, Matthew P; Brautigam, Chad A et al. (2018) Design principles of a microtubule polymerase. Elife 7:
Lang, Jackie; Barber, Adrienne; Biggins, Sue (2018) An assay for de novo kinetochore assembly reveals a key role for the CENP-T pathway in budding yeast. Elife 7:
Gupta, Amitabha; Evans, Rena K; Koch, Lori B et al. (2018) Purification of kinetochores from the budding yeast Saccharomyces cerevisiae. Methods Cell Biol 144:349-370
Suzuki, Aussie; Gupta, Amitabha; Long, Sarah K et al. (2018) A Kinesin-5, Cin8, Recruits Protein Phosphatase 1 to Kinetochores and Regulates Chromosome Segregation. Curr Biol 28:2697-2704.e3
Tubman, Emily S; Biggins, Sue; Odde, David J (2017) Stochastic Modeling Yields a Mechanistic Framework for Spindle Attachment Error Correction in Budding Yeast Mitosis. Cell Syst 4:645-650.e5
Miller, Matthew P; Asbury, Charles L; Biggins, Sue (2016) A TOG Protein Confers Tension Sensitivity to Kinetochore-Microtubule Attachments. Cell 165:1428-1439
Driver, Jonathan W; Powers, Andrew F; Sarangapani, Krishna K et al. (2014) Measuring kinetochore-microtubule interaction in vitro. Methods Enzymol 540:321-37
Sarangapani, Krishna K; Duro, Eris; Deng, Yi et al. (2014) Sister kinetochores are mechanically fused during meiosis I in yeast. Science 346:248-51
London, Nitobe; Biggins, Sue (2014) Signalling dynamics in the spindle checkpoint response. Nat Rev Mol Cell Biol 15:736-47
Umbreit, Neil T; Miller, Matthew P; Tien, Jerry F et al. (2014) Kinetochores require oligomerization of Dam1 complex to maintain microtubule attachments against tension and promote biorientation. Nat Commun 5:4951

Showing the most recent 10 out of 28 publications