The transmission of genetic material in each cell division requires its accurate duplication and distribution to the daughter cells. Errors in this process lead to aneuploidy, which is implicated in oncogenesis, birth defects and cell death. The chromosomes are segregated into two equivalent parts by a microtubule- based molecular machine, the mitotic spindle. The spindle is bipolar with each pole carrying an exact complement of chromosomes to each daughter cell. Chromosomes attach to microtubules via multiprotein organelles called kinetochores. The kinetochore is at the center of both an error correction mechanism and the spindle checkpoint, which delays the cell cycle as long as unattached kinetochores remain. Kinetochores attach to microtubules with a striking combination of strength and plasticity. The attachments are mobile and robust under tension, but can also rapidly destabilize in response to regulatory signals. The binding strength of a native kinetochore is greater than that provided by the sum of its components. We will use reconstitution to test hypotheses for how the attachment strength is enhanced. Kinetochores transmit force from the end of the microtubule to the centromere. A model for the connectivity of the complexes within an assembled kinetochore has been proposed based on data gathered from multiple organisms. We propose to test this model and map the chain of connections that transmit force. Finally, we will test hypotheses for how incorrect attachments are detected and corrected.
The transmission of genetic material in each cell division requires its accurate duplication and distribution to the daughter cells. Errors in this process led to aneuploidy, which is implicated in oncogenesis, disability and cell death.
|Hsia, Yang; Bale, Jacob B; Gonen, Shane et al. (2016) Design of a hyperstable 60-subunit protein icosahedron. Nature 535:136-9|
|Zelter, Alex; Bonomi, Massimiliano; Kim, Jae ook et al. (2015) The molecular architecture of the Dam1 kinetochore complex is defined by cross-linking based structural modelling. Nat Commun 6:8673|
|Kollman, Justin M; Greenberg, Charles H; Li, Sam et al. (2015) Ring closure activates yeast Î³TuRC for species-specific microtubule nucleation. Nat Struct Mol Biol 22:132-7|
|Kudalkar, Emily M; Scarborough, Emily A; Umbreit, Neil T et al. (2015) Regulation of outer kinetochore Ndc80 complex-based microtubule attachments by the central kinetochore Mis12/MIND complex. Proc Natl Acad Sci U S A 112:E5583-9|
|Tien, Jerry F; Umbreit, Neil T; Zelter, Alex et al. (2014) Kinetochore biorientation in Saccharomyces cerevisiae requires a tightly folded conformation of the Ndc80 complex. Genetics 198:1483-93|
|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|
|Tien, Jerry F; Fong, Kimberly K; Umbreit, Neil T et al. (2013) Coupling unbiased mutagenesis to high-throughput DNA sequencing uncovers functional domains in the Ndc80 kinetochore protein of Saccharomyces cerevisiae. Genetics 195:159-70|
|Umbreit, Neil T; Gestaut, Daniel R; Tien, Jerry F et al. (2012) The Ndc80 kinetochore complex directly modulates microtubule dynamics. Proc Natl Acad Sci U S A 109:16113-8|
|Umbreit, Neil T; Davis, Trisha N (2012) Mitosis puts sisters in a strained relationship: force generation at the kinetochore. Exp Cell Res 318:1361-6|
|Asbury, Charles L; Tien, Jerry F; Davis, Trisha N (2011) Kinetochores' gripping feat: conformational wave or biased diffusion? Trends Cell Biol 21:38-46|
Showing the most recent 10 out of 53 publications