The central problems addressed in the proposed research are how the centrosome is assembled, how it duplicates once per cell cycle, and how the """"""""parts list"""""""" for the organelle can be expanded to generate a complete understanding of how it works. The centrosome nucleates microtubules and helps to organize those microtubules to create useful arrays, including the mitotic spindle and the cilium. The centrosome is the major microtubule organizing center in animal cells, and is present in a single copy at the beginning of the cell cycle. The centrosome duplicates in S phase, and the two resulting centrosomes help to organize the two poles of the mitotic spindle. Work from my lab and others over the last ten years has identified molecules involved in microtubule nucleation, the central regulators of centrosome duplication, important structural proteins involved in duplication, and control mechanisms that control centrosome number and link the centrosome and the cell cycle. Interest in the centrosome has grown recently because of the role of a correlation has been established between centrosome abnormalities and the development of cancer. Cancer cells often have extra centrosomes, which is likely to contribute to the genomic instability and rapid evolution characteristic of this disease. The proposed experiments make use of the strengths that we have developed in reagents and assays for studying centrosome structure, function and duplication. We have chosen to focus on the process in animal cells and extracts as they are the systems most relevant to our desire to understand the human centrosome in normal cell division, and in disease. I will address four specific aims in this proposal: 1) Characterize the role of separase in centriole disengagement. 2) Characterize the role of Plk4 in centriole formation 3) Define the interactions responsible for localization of the gammaTuRC to sites of microtubule nucleation. 4) Identify and characterize new centriole and centrosome components in MTEC ciliogenesis dataset

Public Health Relevance

The centrosome is a component of the cell that sits at the center of a network of fibers, microtubules, that perform work within the cell. The centrosome is present in exactly one copy per cell and it duplicates every cell cycle, along with the chromosomes. Failure to control centrosome duplication leads to problems with separation of chromosomes and is associated with cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Nuclear Dynamics and Transport (NDT)
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Gindhart, Joseph G
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Stanford University
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Wang, Jennifer T; Kong, Dong; Hoerner, Christian R et al. (2017) Centriole triplet microtubules are required for stable centriole formation and inheritance in human cells. Elife 6:
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