Regulation of protein ubiquitination in centrosome homeostasis

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The long-term objective of our research program is to understand the controls that regulate the timely destruction of proteins required for cell division. Cell division is a fundamental biological process that occurs in all organisms and requires a specialized cellular component called the centrosome to help distribute identical genetic material, or DNA, into two daughter cells. The number of centrosomes is subjected to tight regulation, and defects in centrosome number or function could induce division failure, resulting in growth inhibition and cell death. For a cell to successfully grow and divide, proteins at the centrosome must execute their functions at the right time and hence, they are continuously being synthesized and degraded. We do not know exactly how many different protein degradation machineries there are at the centrosome, how their functions are controlled, and how many substrates they can recognize and degrade. We recently began to characterize a novel centrosomal component, Cep78, which impinges on the function of a specific type of protein degradation machinery called DEDD. When Cep78 binds to DEDD, substrates that are normally targeted by this machinery for destruction are no longer degraded. Thus, we hypothesize that Cep78 is a novel factor that specifically regulates the activity of DEDD and degradation of associated substrates in a timely manner, and that too much or too little Cep78 can have deleterious consequences on the centrosome. Through two specific aims, we will describe the mechanism by which Cep78 controls DEDD function at the molecular level, identify novel DEDD substrates, and examine the consequences of altering substrate degradation on centrosome number and function. These analyses will provide insights into the role of a novel factor in regulating protein turnover at the centrosome, which is a prerequisite for faithful cell division.**