Molecular biology of microtuble-interacting proteins

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DESCRIPTION (provided by applicant): Project Summary: Polar Microtubule organizing centers (PMTOCs) such as the centrosome and spindle pole body have a well-established role in the nucleation of microtubule assembly in animal and fungal cells. Recent data have suggested, however, that PMTOCs have additional essential roles in the regulation of mitosis and the cell cycle. Although this area is clearly important, most of the results obtained to date are descriptive, and information as to the mechanisms by which PMTOCs participate in mitotic regulation is limited. gamma-Tubulin is a PMTOC protein that plays a critical role in microtubule nucleation. In the current grant period we have studied the effects of gamma-tubulin mutations in the fungus Aspergillus nidulans that inhibit growth at certain temperatures but do not block microtubule assembly. Our results reveal that these gamma- tubulin mutations disrupt the coordination of late mitotic events, chromosomal disjunction, movement of chromosomes to the poles of the mitotic apparatus, and mitotic exit. Our data demonstrate, moreover, that these are not consequences of inadequate microtubule assembly or weak attachment of microtubules to PMTOCs. We believe that these mutations provide valuable tools that allow us to begin to study the mechanisms by which gamma-tubulin and, by extension, PMTOCs participate in mitotic regulation. In the current grant period, we propose to determine which mitotic regulatory pathways are altered by these mutants and how they are altered. We hypothesize that binding of mitotic regulatory proteins to PMTOCs is important for their functioning and that gamma-tubulin mutants may alter the binding of one or more of these proteins. We will, consequently, examine the localization patterns of mitotic regulatory proteins in mitosis. From these data, we expect to be able to determine the mechanisms by which gamma-tubulin functions in mitotic regulation. Relevance: Correct segregation of chromosomes is essential for cellular reproduction and development of all multicellular organisms. Incorrect chromosomal segregation contributes to birth defects and the progression of cells from normal to cancerous. Pathogenic species of Aspergillus are a major cause of mortality in immune-compromised patients.