Each cell in the human body contains 46 different chromosomes, large units of DNA that encode instructions for that cell to grow, divide, and carry out its specialized functions. During mitosis, when a cell divides, each of these chromosomes must be accurately distributed to the two new daughter cells. If this process occurs incorrectly for even a single chromosome, the resulting daughter cells will lose or gain thousands of genes and the instructions that they contain. This type of error in chromosome segregation can result in the death of the cell and is thought to contribute to tumorigenesis. Indeed, as many as 70% of tumors are observed to have abnormal numbers of chromosomes. To facilitate the segregation of DNA during mitosis, chromosomes must generate physical attachments to rod-like polymers termed microtubules that provide the structure and forces to move the chromosomes. Anti-mitotic drugs that disrupt the ability of these microtubules to connect with the chromosomes are routinely used for cancer chemotherapy. However, many of these drugs have deleterious secondary affects due to additional roles for microtubules in the nervous system. A key player in chromosome segregation is a large proteinaceous structure termed the kinetochore that forms the interface between the chromosomes and the microtubules. Inhibition of kinetochore activities is predicted target cancer cells while avoiding the dose-limiting neuronal toxicity associated with microtubule-binding chemotherapy drugs. Indeed, inhibitors against several kinetochore proteins are currently in clinical trials. Determining the specific activities of each human kinetochore protein is crucial to provide a context for their functions in chromosome segregation, to evaluate the best targets for the diagnosis and treatment of disease, and to generate assays suitable for the isolation of small molecule inhibitors. The proposed work will analyze the function and regulation of the human kinetochore proteins that are required to generate interactions with microtubules. This work will focus on two key, recently identified groups of kinetochore-associated proteins that bind to microtubule polymers directly. These studies will define the properties of these proteins and determine the mechanisms by which these proteins interact with microtubules, dissect their regulation by upstream kinases that control kinetochore-microtubule attachments, and examine their functions in human cells. In total, these studies will define the basis for kinetochore-microtubule interactions that will ultimately provide the foundation for experiments on the diagnosis and treatment of cancer.
Project Narrative Defects in mitosis that result in errors in chromosome numbers can cause the death of a cell and are thought to contribute to tumor progression. Understanding the means by which these units of DNA, and the genetic information that they contain, are evenly distributed to new cells is critical for the diagnosis and treatment of cancer. This proposed work will determine the mechanisms that direct and control chromosome segregation in human cells.
|Monda, Julie K; Whitney, Ian P; Tarasovetc, Ekaterina V et al. (2017) Microtubule Tip Tracking by the Spindle and Kinetochore Protein Ska1 Requires Diverse Tubulin-Interacting Surfaces. Curr Biol 27:3666-3675.e6|
|Kern, David M; Monda, Julie K; Su, Kuan-Chung et al. (2017) Astrin-SKAP complex reconstitution reveals its kinetochore interaction with microtubule-bound Ndc80. Elife 6:|
|McKinley, Kara L; Cheeseman, Iain M (2017) Large-Scale Analysis of CRISPR/Cas9 Cell-Cycle Knockouts Reveals the Diversity of p53-Dependent Responses to Cell-Cycle Defects. Dev Cell 40:405-420.e2|
|McKinley, Kara L; Cheeseman, Iain M (2016) The molecular basis for centromere identity and function. Nat Rev Mol Cell Biol 17:16-29|
|Su, Kuan-Chung; Barry, Zachary; Schweizer, Nina et al. (2016) A Regulatory Switch Alters Chromosome Motions at the Metaphase-to-Anaphase Transition. Cell Rep 17:1728-1738|
|Wilson-Kubalek, Elizabeth M; Cheeseman, Iain M; Milligan, Ronald A (2016) Structural comparison of the Caenorhabditis elegans and human Ndc80 complexes bound to microtubules reveals distinct binding behavior. Mol Biol Cell 27:1197-203|
|Kern, David M; Nicholls, Peter K; Page, David C et al. (2016) A mitotic SKAP isoform regulates spindle positioning at astral microtubule plus ends. J Cell Biol 213:315-28|
|Monnier, Nilah; Barry, Zachary; Park, Hye Yoon et al. (2015) Inferring transient particle transport dynamics in live cells. Nat Methods 12:838-40|
|Kern, David M; Kim, Taekyung; Rigney, Mike et al. (2015) The outer kinetochore protein KNL-1 contains a defined oligomerization domain in nematodes. Mol Biol Cell 26:229-37|
|McKinley, Kara L; Sekulic, Nikolina; Guo, Lucie Y et al. (2015) The CENP-L-N Complex Forms a Critical Node in an Integrated Meshwork of Interactions at the Centromere-Kinetochore Interface. Mol Cell 60:886-98|
Showing the most recent 10 out of 36 publications