Regulation of protein ubiquitination in centrosome homeostasis

中心体稳态中蛋白质泛素化的调节

• 批准号: RGPIN-2016-04002
• 负责人: Tsang, William
• 金额: $ 2.26万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614773
• 关键词: Regulation; protein; ubiquitination; centrosome; homeostasis

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.

我们研究计划的长期目标是了解调节细胞分裂所需蛋白质及时破坏的控制。细胞分裂是一个基本的生物学过程，发生在所有生物体中，需要一个专门的细胞成分称为中心体，以帮助分配相同的遗传物质，或DNA，到两个子细胞。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诱导分裂失败，导致生长抑制和细胞死亡。为了使细胞成功地生长和分裂，中心体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。我们不知道中心体上到底有多少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。我们最近开始表征一种新的中心体成分Cep78，它影响一种称为DEDD的特定类型的蛋白质降解机制的功能。当Cep78与DEDD结合时，通常被这种机制靶向破坏的底物不再降解。因此，我们假设Cep78是一种新的因子，它特异性地调节DEDD的活性和相关底物的降解，并且太多或太少的Cep78会对中心体产生有害的后果。通过两个具体的目标，我们将描述Cep78在分子水平上控制DEDD功能的机制，确定新的DEDD底物，并研究改变底物降解对中心体数量和功能的影响。这些分析将提供一个新的因素在调节中心体蛋白质周转的作用，这是一个忠实的细胞分裂的先决条件的见解。