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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088313-04
Application #
8299046
Study Section
Nuclear Dynamics and Transport (NDT)
Program Officer
Deatherage, James F
Project Start
2009-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$363,127
Indirect Cost
$176,908
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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McKinley, Kara L; Cheeseman, Iain M (2014) Polo-like kinase 1 licenses CENP-A deposition at centromeres. Cell 158:397-411
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
Gascoigne, Karen E; Cheeseman, Iain M (2013) Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis. Chromosome Res 21:407-18
Kiyomitsu, Tomomi; Cheeseman, Iain M (2013) Cortical dynein and asymmetric membrane elongation coordinately position the spindle in anaphase. Cell 154:391-402
Nishino, Tatsuya; Rago, Florencia; Hori, Tetsuya et al. (2013) CENP-T provides a structural platform for outer kinetochore assembly. EMBO J 32:424-36
Rago, Florencia; Cheeseman, Iain M (2013) Review series: The functions and consequences of force at kinetochores. J Cell Biol 200:557-65
Earnshaw, W C; Allshire, R C; Black, B E et al. (2013) Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant. Chromosome Res 21:101-6
Gascoigne, Karen E; Cheeseman, Iain M (2013) CDK-dependent phosphorylation and nuclear exclusion coordinately control kinetochore assembly state. J Cell Biol 201:23-32
Backer, Chelsea B; Gutzman, Jennifer H; Pearson, Chad G et al. (2012) CSAP localizes to polyglutamylated microtubules and promotes proper cilia function and zebrafish development. Mol Biol Cell 23:2122-30

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