The precise partitioning of duplicated chromosomes to daughter cells is essential for the development and survival of all organisms. Defects in segregation lead to aneuploidy, the state where entire chromosomes are gained or lost. Aneuploidy is a hallmark of the majority of tumor cells and has been postulated to be a major factor in the evolution of cancer. Aneuploidy is also the leading cause of spontaneous miscarriages and hereditary birth defects in humans. The goal of this proposal is to elucidate the mechanisms that regulate chromosome segregation and therefore ensure genomic stability. Chromosome segregation requires forces generated by spindle microtubules that are translated into chromosome movement through interactions with kinetochores, the highly conserved structures that assemble onto centromeric chromatin. The simplest eukaryotic kinetochore is in budding yeast where ~38 unique 'core'proteins that exist in 8 subcomplexes assemble into a structure estimated to be >5 MDa. Accurate segregation requires kinetochores to maintain load-bearing attachments to the ends of microtubules that are continually growing and shrinking. Key to proper segregation is the ability of sister kinetochores to biorient and attach to microtubules from opposite poles. Kinetochores also engage a highly conserved signal transduction system called the spindle checkpoint to halt the cell cycle when kinetochore-microtubule interactions are aberrant. To fully elucidate the mechanisms that ensure faithful chromosome segregation, it is critical to understand the diverse functions of kinetochores and their regulation. This proposal will use purified kinetochores and a combination of biochemical, biophysical and structural approaches to address a number of outstanding questions: 1) How does phosphorylation regulate the diverse functions of kinetochores? 2) How do kinetochores regulate the spindle checkpoint? and 3) What is the architecture of a yeast kinetochore? The proposal will use budding yeast for these studies because they are amenable to biochemical, genetic and cytological studies, and the yeast kinetochore is the best characterized to date. Taken together, these studies of kinetochores and their regulation in budding yeast will lead toward an understanding of the fundamental mechanisms of segregation in all eukaryotes. This work will not only elucidate important aspects about the process of segregation, but will aid in the design of better therapeutic interventions in the long-term.

Public Health Relevance

All cells must inherit the right number of chromosomes every time they divide because the wrong number of chromosomes is a hallmark of cancer and birth defects. We are therefore studying the process of chromosome partitioning to daughter cells when they divide to understand the basis for a number of human diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
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Deatherage, James F
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Fred Hutchinson Cancer Research Center
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Miller, Matthew P; Asbury, Charles L; Biggins, Sue (2016) A TOG Protein Confers Tension Sensitivity to Kinetochore-Microtubule Attachments. Cell 165:1428-1439
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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) Mad1 kinetochore recruitment by Mps1-mediated phosphorylation of Bub1 signals the spindle checkpoint. Genes Dev 28:140-52
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
London, Nitobe; Biggins, Sue (2014) Signalling dynamics in the spindle checkpoint response. Nat Rev Mol Cell Biol 15:736-47
Biggins, Sue (2013) The composition, functions, and regulation of the budding yeast kinetochore. Genetics 194:817-46
Akiyoshi, Bungo; Nelson, Christian R; Biggins, Sue (2013) The aurora B kinase promotes inner and outer kinetochore interactions in budding yeast. Genetics 194:785-9
Sarangapani, Krishna K; Akiyoshi, Bungo; Duggan, Nicole M et al. (2013) Phosphoregulation promotes release of kinetochores from dynamic microtubules via multiple mechanisms. Proc Natl Acad Sci U S A 110:7282-7
Akiyoshi, Bungo; Nelson, Christian R; Duggan, Nicole et al. (2013) The Mub1/Ubr2 ubiquitin ligase complex regulates the conserved Dsn1 kinetochore protein. PLoS Genet 9:e1003216

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