The role of CENP-A in mammalian centromere specification

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DESCRIPTION (provided by applicant): In order for sister chromosomes to be faithfully segregated to opposing daughter cells during cell division, each chromosome must possess a single centromere. The lack of a centromere or the creation of dicentric chromosomes (those possessing two centromeres) leads to chromosomal breakage and missegregation of chromosomes during mitosis. In turn, aberrant chromosome segregation may give rise to developmental abnormalities and neoplastic disease. Furthermore, a better understanding of the components of the human chromosome that govern transmission of genetic information may be important in the development of novel gene therapies. Specific Aim 1: By developing a transgenic mouse containing a conditional disruption of the endogenous mouse CENP-A gene, these studies seek to determine whether CENP-A protein is required for the establishment and maintenance of the mammalian centromere. Specific Aim 2: Furthermore, using a yeast two-hybrid screen, this study endeavors to identify proteins that interact with CENP-A that may be involved in centromere specification and kinetochore assembly. Specific Aim3: Finally, the studies proposed here are designed to determine whether CENP-A itself is sufficient to recruit centromere components and ultimately specify the centromere.