Equal chromosome segregation in mitosis requires proper interaction between the chromosomes and the mitotic spindle. Kinetochores are the specialized structures that are assembled on centromeric DNAs and mediate the attachment between the chromosomes and the spindle microtubules. Kinetochores of various organisms differ remarkably in their architectures and yet perform fundamentally similar functions. Much has been learnt of the kinetochores in S. cerevisiae. However, it is unclear to what extent can we apply the knowledge of this simple point kinetochore onto complex regional kinetochores such as those of humans. The long-term goal of this proposal is to dissect the kinetochore structure in S. pombe as a model of the regional kinetochores and to understand how kinetochores co-ordinate with the spindle to ensure the high fidelity of chromosome segregation in this model organism. By comparing and contrasting the kinetochores of S. pombe, S. cerevisiae and those of other organisms, we wish to delineate the general biological principles of the kinetochore functions. This knowledge will facilitate the identification of the molecular lesions in tumor cells which lead to high rate of aneuploidy - erroneous chromosome numbers that are detected in virtually all types of tumor.
Three specific aims are proposed here to analyze the kinetochore/spindle interaction in fission yeast: 1. To identify novel kinetochore and spindle components in fission yeast that are required for their proper attachment. 2. To characterize the architectural and functional roles of novel kinetochore proteins. 3. To explore the mechanism of how kinetochores switch from a static affinity to spindle pole to a dynamic affinity to spindle MTs at the entry of mitosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM068676-02
Application #
6784120
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Deatherage, James F
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$263,375
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Yao, Jianhui; Liu, Xingkun; Sakuno, Takeshi et al. (2013) Plasticity and epigenetic inheritance of centromere-specific histone H3 (CENP-A)-containing nucleosome positioning in the fission yeast. J Biol Chem 288:19184-96
Li, Zao; Lu, Nan; He, Xiangwei et al. (2013) Monitoring the clearance of apoptotic and necrotic cells in the nematode Caenorhabditis elegans. Methods Mol Biol 1004:183-202
Xi, Yuanxin; Yao, Jianhui; Chen, Rui et al. (2011) Nucleosome fragility reveals novel functional states of chromatin and poises genes for activation. Genome Res 21:718-24
Gao, Qi; Courtheoux, Thibault; Gachet, Yannick et al. (2010) A non-ring-like form of the Dam1 complex modulates microtubule dynamics in fission yeast. Proc Natl Acad Sci U S A 107:13330-5
Pidoux, Alison L; Choi, Eun Shik; Abbott, Johanna K R et al. (2009) Fission yeast Scm3: A CENP-A receptor required for integrity of subkinetochore chromatin. Mol Cell 33:299-311
Lu, Nan; Yu, Xiaomeng; He, Xiangwei et al. (2009) Detecting apoptotic cells and monitoring their clearance in the nematode Caenorhabditis elegans. Methods Mol Biol 559:357-70
Joglekar, Ajit P; Bouck, David; Finley, Ken et al. (2008) Molecular architecture of the kinetochore-microtubule attachment site is conserved between point and regional centromeres. J Cell Biol 181:587-94
Song, Jun S; Liu, Xingkun; Liu, X Shirley et al. (2008) A high-resolution map of nucleosome positioning on a fission yeast centromere. Genome Res 18:1064-72
Lafuente, Esther M; van Puijenbroek, Andre A F L; Krause, Matthias et al. (2004) RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell 7:585-95