Structural mechanisms of centriole assembly during cell duplication

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From embryo to adulthood and every day of our lives we rely on the normal growth and division of millions of cells. For each cell division our genetic material, packed in chromosomes, must also properly divide. In humans and animals this is achieved by an elaborate structure, called the nuclear spindle, organized by copies of the centrosome at each end of the cell. After division, each new cell has only one centrosome; therefore it must duplicate in order for further cell divisions to occur. Centrosome duplication is a process for which we have relatively little information. We know that any abnormalities in this process can cause diseases or even cancer; however we do not know how this process is regulated, what is the role of each individual centrosomal component or how they assemble together. If we could understand how centrosome duplication takes place and how abnormalities can occur, then we could possibly devise treatments or new drugs. Therefore, there is much interest in understanding this process at the most detailed level possible.We propose to use a combination of approaches, including cell biology, microscopy and biophysics to answer specific questions about the centrosome duplication process. We are interested in how their elaborate 9-fold symmetric shape is defined, and whether this is achieved by the same method in all organisms or whether there are significant differences. We would like to study how the cells control the start of the duplication process to ensure that it only happens once per cell division. Finally, we aim to find the correct place in the assembly for the various centrosomal components, similar to pieces in a puzzle. The centrosome is a molecular machine, composed of many large proteins. To be able to study these components in sufficient detail, we first aim to find smaller, functional subunits, which we can analyze with biophysical tools. We can then make predictions for the properties of whole components based on these individual fragments, and test these predictions using electron microscopy and cell biology. Some important aspects of this work require expertise not present in our core group. Therefore we collaborate with internationally recognized groups in the UK and abroad to access the broadest base of expertise possible.