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, more than 70% of tumors are observed to have abnormal numbers of chromosomes. In addition to errors that alter whole chromosome numbers, in cases where the cellular machinery makes inappropriate attachments to the chromosomes, this can result in chromosome fragmentation during cell division. These errors have been shown to cause chromosomal rearrangements, which also have the potential to result in cellular transformation and tumorigenesis. 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. A key player in chromosome segregation is a large proteinaceous structure termed the kinetochore that forms the interface between chromosomes and microtubules. Inhibition of kinetochore activities is predicted to target cancer cells while avoiding the dose-limiting neuronal toxicity associated with microtubule-binding chemotherapeutics. Determining the molecular basis for kinetochore function is crucial to understand the defective processes that can give rise to tumor cells, and to evaluate the best targets for the diagnosis and treatment of disease. The proposed work will analyze the mechanisms by which kinetochores interact with spindle microtubule polymers in human cells. We will take parallel cellular and biochemical approaches to analyze the key proteins that bind to microtubules at kinetochores. A key focus of this work will be not only to analyze the functions and activities of the individual proteins, but also to test how the multiple different proteins that are present at kinetochores act together in a integrated manner to form robust interactions with microtubules.

Public Health Relevance

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 by analyzing the connections between chromosomes and the rod-like microtubule polymers that provide the structure and force to segregate the DNA.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM088313-06
Application #
8755297
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Deatherage, James F
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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
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
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
Rago, Florencia; Gascoigne, Karen E; Cheeseman, Iain M (2015) Distinct organization and regulation of the outer kinetochore KMN network downstream of CENP-C and CENP-T. Curr Biol 25:671-7
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
Boeszoermenyi, Andras; Schmidt, Jens C; Cheeseman, Iain M et al. (2014) Resonance assignments of the microtubule-binding domain of the C. elegans spindle and kinetochore-associated protein 1. Biomol NMR Assign 8:275-8
Thiru, Prathapan; Kern, David M; McKinley, Kara L et al. (2014) Kinetochore genes are coordinately up-regulated in human tumors as part of a FoxM1-related cell division program. Mol Biol Cell 25:1983-94

Showing the most recent 10 out of 33 publications