Regulation of protein ubiquitination in centrosome homeostasis

我们研究计划的长期目标是了解调控细胞分裂所需蛋白质及时破坏的控制措施。细胞分裂是所有生物体都会发生的基本生物学过程，需要一种名为中心体的特殊细胞成分来帮助将相同的遗传物质或DNA分配到两个子细胞中。中心体的数量受到严格的调控，中心体数量或功能的缺陷可能导致分裂失败，导致生长抑制和细胞死亡。为了细胞的成功生长和分裂，中心体上的蛋白质必须在正确的时间执行它们的功能，因此，它们不断地被合成和降解。我们不知道在中心体有多少种不同的蛋白质降解机制，它们的功能是如何控制的，以及它们可以识别和降解多少底物。我们最近开始鉴定一种新的中心体成分Cep78，它影响一种名为DEDD的特定类型的蛋白质降解机制的功能。当Cep78与DEDD结合时，通常被该机器破坏的底物不再被降解。因此，我们假设Cep78是一种新的因子，它能及时特异地调节DEDD的活性和相关底物的降解，Cep78过多或过少都会对中心体产生有害后果。通过两个特定的目标，我们将描述Cep78在分子水平上控制DEDD功能的机制，寻找新的DEDD底物，并研究改变底物降解对中心体数量和功能的影响。这些分析将为一种新因素在调节中心体蛋白质周转中的作用提供洞察力，中心体蛋白质周转是细胞有效分裂的先决条件。

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.