This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Improper maintenance of ploidy (chromosome number) is a hallmark of many cancer cell types, and is thought to contribute to the malignancy of cancer cell populations. In a number of tumors tetraploidy (exactly twice the normal chromosome number) precedes a more degenerate state, in which individual chromosomes are lost or gained at random. With this project we begin an investigation of a particular chromosomal arrangement that forms in some tetraploid cells, called a diplochromosome. Diplochromosomes are most commonly seen in tumor cells, in cells that have been treated with certain kinds of poisons, and in cells from individuals with defects in sister chromatid cohesion. The conditions that lead to diplochromosome formation are not understood. The segregation of diplochromosomes when cells divide has not been investigated in detail, but studies in some organisms suggest that it is highly error-prone. Thus diplochromosomes might contribute to development of the CIN phenotype, and explain the connection between tetraploidy and malignancy. The significance of the presence of diplochromosomes, and the factors that contribute to their formation, have not been investigated. This project includes experiments that will allow us to begin to address both issues. We will also determine the segregation behavior of diplochromosomes at cell division. With these experiments we will increase our understanding of the etiology of certain human developmental disorders, in which decreased sister chromatid cohesion leads both to formation of diplochromosome-containing cells and increased incidence of cancer.
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