CELL CYCLE REGULATION OF GOLGI MEMBRANE DYNAMICS

Ut Southwestern Medical Center, Dallas TX

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Abstract

? DESCRIPTION (provided by applicant): Cell proliferation critically depends on the duplication organelles in interphase and the segregation between the two daughter cells during mitosis. Accurate partitioning of chromosomes and intracellular organelles is crucial to sustain cellular functions over generations. Defects in mitosis can lead to genomic instability and loss of vital organelles, which is commonly associated with the development of cancer. While much progress has been made towards understanding the segregation of chromosomes, the mechanisms that govern the partitioning of vital organelles, in particular of the Golgi, remain largely unknown. The mammalian Golgi is essential for secretion and post-mitotic cell survival depends on the partitioning of a functional Golgi into progeny. Our aim is to define the underlying mechanisms that ensure the faithful partitioning of the single mammalian Golgi during mitosis. At the onset of mitosis, the highly organized Golgi structure vesiculates and reforms after equal partitioning in the two daughter cells. We previously showed that the spindle actively partitions the mammalian Golgi. This process is initiated by the Golgi membrane protein GM130, which locally activates the spindle assembly factor TPX2 to initiate microtubule polymerization. Forming microtubules are further captured and bundled by GM130, thereby linking Golgi membranes to the spindle to ensure the Golgi segregation into the daughter cells. In this proposal we plan to determine the biochemical and mechanistic basis for this process. Our aims are to determine the molecular basis for binding partner and functional switching of GM130 in mitosis; to dissect GM130 functions in microtubule nucleation, bundling and Ran dependency in Golgi-derived spindle assembly; and to elucidate the role of Golgi vesiculation in mitotic progression. Together these studies will provide new molecular mechanistic insights into the regulation of mitosis and the division process of the Golgi apparatus.