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. 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. Chromosomes segregate using their kinetochores, the specialized protein structures that are assembled on centromeric DNA sequences and mediate attachment to the spindle. Because centromeric DNA sequences are not conserved, centromere identity is propagated by an epigenetic mechanism. A hallmark of epigenetic regulation is a specialized chromatin structure that is characterized by the presence of histone variants and unique post-translational modifications to histones. Consistent with this, all eukaryotic centromeres contain an essential histone H3 variant (CenH3) that is required for kinetochore assembly and is likely to be the epigenetic mark that specifies centromere identity. In addition, the H2A.Z histone variant localizes to pericentromeric and centromeric chromatin in a number of organisms, and centromeres contain a distinct histone modification pattern relative to euchromatin. Although a specialized chromatin structure is essential for centromere identity and function, the mechanisms that assemble and maintain centromeric chromatin have not been elucidated. We will therefore take complementary biochemical and genetic approaches to identify factors that deposit CenH3 at centromeres. In addition, we will identify the mechanisms that maintain CenH3 at the centromere and prevent it from localizing to euchromatin. Finally, we have developed a method to enrich for histones associated with centromeres that will allows us to identify centromere-specific histone modifications that are important for chromosome segregation. Taken together, these studies will lead to a better understanding of chromosome segregation and the maintenance of centromere identity and genomic stability in all eukaryotes. Project Narrative All cells must inherit the right number of chromosomes every time they divide because the wrong number of chromosomes is a hallmark of all cancers and a number of 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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Molecular Genetics C Study Section (MGC)
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Carter, Anthony D
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Fred Hutchinson Cancer Research Center
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Deyter, Gary M R; Hildebrand, Erica M; Barber, Adrienne D et al. (2017) Histone H4 Facilitates the Proteolysis of the Budding Yeast CENP-ACse4 Centromeric Histone Variant. Genetics 205:113-124
Hildebrand, Erica M; Biggins, Sue (2016) Regulation of Budding Yeast CENP-A levels Prevents Misincorporation at Promoter Nucleosomes and Transcriptional Defects. PLoS Genet 12:e1005930
Driver, Jonathan W; Powers, Andrew F; Sarangapani, Krishna K et al. (2014) Measuring kinetochore-microtubule interaction in vitro. Methods Enzymol 540:321-37
Biggins, Sue; Welch, Matthew D (2014) Editorial overview: Cell architecture: Cellular organization and function. Curr Opin Cell Biol 26:v-vii
Deyter, Gary M R; Biggins, Sue (2014) The FACT complex interacts with the E3 ubiquitin ligase Psh1 to prevent ectopic localization of CENP-A. Genes Dev 28:1815-26
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
Ng, Tessie M; Lenstra, Tineke L; Duggan, Nicole et al. (2013) Kinetochore function and chromosome segregation rely on critical residues in histones H3 and H4 in budding yeast. Genetics 195:795-807
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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